bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2020–10–11
78 papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. In vivo CRISPR/Cas9 targeting of fusion oncogenes for selective elimination of cancer cells.
  2. Disturbed mitochondrial dynamics in CD8+ TILs reinforce T cell exhaustion.
  3. Phosphorylation of PDHA by AMPK Drives TCA Cycle to Promote Cancer Metastasis.
  4. Respiratory Supercomplexes Promote Mitochondrial Efficiency and Growth in Severely Hypoxic Pancreatic Cancer.
  5. Lactate Elicits ER-Mitochondrial Mg2+ Dynamics to Integrate Cellular Metabolism.
  6. Multiregion whole-exome sequencing of intraductal papillary mucinous neoplasms reveals frequent somatic KLF4 mutations predominantly in low-grade regions.
  7. Glycolysis regulates Hedgehog signalling via the plasma membrane potential.
  8. CDKN1B/p27 regulates autophagy via the control of Ragulator and MTOR activity in amino acid-deprived cells.
  9. The P2X7 ion channel is dispensable for energy and metabolic homeostasis of white and brown adipose tissues.
  10. Integrins Control Vesicular Trafficking; New Tricks for Old Dogs.
  11. Modulating pyrimidine ribonucleotide levels for the treatment of cancer.
  12. Yeast FIT2 homolog is necessary to maintain cellular proteostasis and membrane lipid homeostasis.
  13. FAK activity in cancer-associated fibroblasts is a prognostic marker and a druggable key metastatic player in pancreatic cancer.
  14. One-Step High-Throughput Telomerase Activity Measurement of Cell Populations, Single Cells, and Single-Enzyme Complexes.
  15. The glucose-sensing transcription factor ChREBP is targeted by proline hydroxylation.
  16. Adaptation and selection shape clonal evolution of tumors during residual disease and recurrence.
  17. Concepts of extracellular matrix remodelling in tumour progression and metastasis.
  18. Breast cancer-associated macrophages promote tumorigenesis by suppressing succinate dehydrogenase in tumor cells.
  19. Reduced mitochondrial translation prevents diet-induced metabolic dysfunction but not inflammation.
  20. Protein Quality Control and Lipid Droplet Metabolism.
  21. Effect of germline mutations in homologous recombination repair genes on overall survival of patients with pancreatic adenocarcinoma.
  22. Heat shock protein-90 inhibition alters activation of pancreatic stellate cells and enhances the efficacy of PD-1 blockade in pancreatic cancer.
  23. Autophagy facilitates adaptation of budding yeast to respiratory growth by recycling serine for one-carbon metabolism.
  24. Clinical utility of circulating tumor DNA sequencing in advanced gastrointestinal cancer: SCRUM-Japan GI-SCREEN and GOZILA studies.
  25. TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS.
  26. Mapping metabolic oscillations during cell cycle progression.
  27. Mechanoactivation of NOX2-generated ROS elicits persistent TRPM8 Ca2+ signals that are inhibited by oncogenic KRas.
  28. When Endoplasmic Reticulum Proteostasis Meets the DNA Damage Response.
  29. Mutant SF3B1 promotes AKT and NF-kB driven mammary tumorigenesis.
  30. RAC1 induces nuclear alterations through the LINC complex to enhance melanoma invasiveness.
  31. Targeting metabolic pathways for extension of lifespan and healthspan across multiple species.
  32. Collagen-rich omentum is a premetastatic niche for integrin α2-mediated peritoneal metastasis.
  33. Immunometabolism in the Single-Cell Era.
  34. A 3D atlas of the dynamic and regional variation of pancreatic innervation in diabetes.
  35. Development and validation of a metastasis-related Gene Signature for predicting the Overall Survival in patients with Pancreatic Ductal Adenocarcinoma.
  36. Walking with Salamanders: From Molecules to Biorobotics.
  37. Field carcinogenesis in cancer evolution: what the cell is going on?
  38. RUNX1 marks a luminal castration resistant lineage established at the onset of prostate development.
  39. Exposure to Static Magnetic and Electric Fields Treats Type 2 Diabetes.
  40. A2A Receptor Activation Attenuates Hypertensive Cardiac Remodeling via Promoting Brown Adipose Tissue-Derived FGF21.
  41. eIF2α controls memory consolidation via excitatory and somatostatin neurons.
  42. The Structure of Human ATG9A and Its Interplay with the Lipid Bilayer.
  43. Ras, PI3K and mTORC2 - three's a crowd?
  44. Metabolic benefits of mitochondrial DNA mutations.
  45. Cancer progression and the invisible phase of metastatic colonization.
  46. How the T cell signaling network processes information to discriminate between self and agonist ligands.
  47. Chronicling changes in the somatosensory neurons after peripheral nerve injury.
  48. Non-genetic mechanisms of therapeutic resistance in cancer.
  49. Tracing the cellular basis of islet specification in mouse pancreas.
  50. Predicting cell-to-cell communication networks using NATMI.
  51. How Lysosomes Sense, Integrate, and Cope with Stress.
  52. The multifaceted role of cell cycle regulators in the coordination of growth and metabolism.
  53. Calreticulin promotes EMT in pancreatic cancer via mediating Ca2+ dependent acute and chronic endoplasmic reticulum stress.
  54. Membrane Biology: Disentangling Cellular Lipid Connections.
  55. Suppression of pancreatic cancer liver metastasis by secretion-deficient ITIH5.
  56. Secretory autophagy machinery and vesicular trafficking are involved in HMGB1 secretion.
  57. Kill one or kill the many: interplay between mitophagy and apoptosis.
  58. Endocytosis in the adaptation to cellular stress.
  59. The hepatic microenvironment uniquely protects leukemia cells through induction of growth and survival pathways mediated by LIPG.
  60. Extracellular matrix plasticity as a driver of cell spreading.
  61. Respiratory supercomplexes enhance electron transport by decreasing cytochrome c diffusion distance.
  62. Lysosome Fusion Maintains Phagosome Integrity during Fungal Infection.
  63. A powerful drug combination strategy targeting glutamine addiction for the treatment of human liver cancer.
  64. Early onset of planet formation observed in a nascent star system.
  65. Topographical Distribution and Spatial Interactions of Innate and Semi-Innate Immune Cells in Pancreatic and Other Periampullary Adenocarcinoma.
  66. Sestrin family - the stem controlling healthy ageing.
  67. Physical Activity and Healthy Aging.
  68. A roadmap for the early detection and diagnosis of cancer.
  69. High G2M Pathway Score Pancreatic Cancer is Associated with Worse Survival, Particularly after Margin-Positive (R1 or R2) Resection.
  70. Artificial selection for host resistance to tumour growth and subsequent cancer cell adaptations: an evolutionary arms race.
  71. Pioneers of revolutionary CRISPR gene editing win chemistry Nobel.
  72. Ratchetaxis in Channels: Entry Point and Local Asymmetry Set Cell Directions in Confinement.
  73. Muscle-Organ Crosstalk: Focus on Immunometabolism.
  74. Design and clinical implementation of an open-source bionic leg.
  75. Dietary thiamine influences l-asparaginase sensitivity in a subset of leukemia cells.
  76. Top 20 translational researchers of 2019.
  77. Virologists who discovered hepatitis C win medicine Nobel.
  78. State of the Art in Exocrine Pancreatic Insufficiency.
  1. Nat Commun. 2020 10 08. 11(1): 5060
    In vivo CRISPR/Cas9 targeting of fusion oncogenes for selective elimination of cancer cells.
    M Martinez-Lage, R Torres-Ruiz, P Puig-Serra, P Moreno-Gaona, M C Martin, F J Moya, O Quintana-Bustamante, S Garcia-Silva, A M Carcaboso, P Petazzi, C Bueno, J Mora, H Peinado, J C Segovia, P Menendez, S Rodriguez-Perales.
      Fusion oncogenes (FOs) are common in many cancer types and are powerful drivers of tumor development. Because their expression is exclusive to cancer cells and their elimination induces cell apoptosis in FO-driven cancers, FOs are attractive therapeutic targets. However, specifically targeting the resulting chimeric products is challenging. Based on CRISPR/Cas9 technology, here we devise a simple, efficient and non-patient-specific gene-editing strategy through targeting of two introns of the genes involved in the rearrangement, allowing for robust disruption of the FO specifically in cancer cells. As a proof-of-concept of its potential, we demonstrate the efficacy of intron-based targeting of transcription factors or tyrosine kinase FOs in reducing tumor burden/mortality in in vivo models. The FO targeting approach presented here might open new horizons for the selective elimination of cancer cells.
    DOI:  https://doi.org/10.1038/s41467-020-18875-x
  2. Nat Immunol. 2020 Oct 05.
    Disturbed mitochondrial dynamics in CD8+ TILs reinforce T cell exhaustion.
    Yi-Ru Yu, Hana Imrichova, Haiping Wang, Tung Chao, Zhengtao Xiao, Min Gao, Marcela Rincon-Restrepo, Fabien Franco, Raphael Genolet, Wan-Chen Cheng, Camilla Jandus, George Coukos, Yi-Fan Jiang, Jason W Locasale, Alfred Zippelius, Pu-Ste Liu, Li Tang, Christoph Bock, Nicola Vannini, Ping-Chih Ho.
      The metabolic challenges present in tumors attenuate the metabolic fitness and antitumor activity of tumor-infiltrating T lymphocytes (TILs). However, it remains unclear whether persistent metabolic insufficiency can imprint permanent T cell dysfunction. We found that TILs accumulated depolarized mitochondria as a result of decreased mitophagy activity and displayed functional, transcriptomic and epigenetic characteristics of terminally exhausted T cells. Mechanistically, reduced mitochondrial fitness in TILs was induced by the coordination of T cell receptor stimulation, microenvironmental stressors and PD-1 signaling. Enforced accumulation of depolarized mitochondria with pharmacological inhibitors induced epigenetic reprogramming toward terminal exhaustion, indicating that mitochondrial deregulation caused T cell exhaustion. Furthermore, supplementation with nicotinamide riboside enhanced T cell mitochondrial fitness and improved responsiveness to anti-PD-1 treatment. Together, our results reveal insights into how mitochondrial dynamics and quality orchestrate T cell antitumor responses and commitment to the exhaustion program.
    DOI:  https://doi.org/10.1038/s41590-020-0793-3
  3. Mol Cell. 2020 Sep 29. pii: S1097-2765(20)30648-1. [Epub ahead of print]
    Phosphorylation of PDHA by AMPK Drives TCA Cycle to Promote Cancer Metastasis.
    Zhen Cai, Chien-Feng Li, Fei Han, Chunfang Liu, Anmei Zhang, Che-Chia Hsu, Danni Peng, Xian Zhang, Guoxiang Jin, Abdol-Hossein Rezaeian, Guihua Wang, Weina Zhang, Bo-Syong Pan, Chi-Yun Wang, Yu-Hui Wang, Shih-Ying Wu, Shun-Chin Yang, Fang-Chi Hsu, Ralph B D'Agostino, Christina M Furdui, Gregory L Kucera, John S Parks, Floyd H Chilton, Chih-Yang Huang, Fuu-Jen Tsai, Boris Pasche, Kounosuke Watabe, Hui-Kuan Lin.
      Cancer metastasis accounts for the major cause of cancer-related deaths. How disseminated cancer cells cope with hostile microenvironments in secondary site for full-blown metastasis is largely unknown. Here, we show that AMPK (AMP-activated protein kinase), activated in mouse metastasis models, drives pyruvate dehydrogenase complex (PDHc) activation to maintain TCA cycle (tricarboxylic acid cycle) and promotes cancer metastasis by adapting cancer cells to metabolic and oxidative stresses. This AMPK-PDHc axis is activated in advanced breast cancer and predicts poor metastasis-free survival. Mechanistically, AMPK localizes in the mitochondrial matrix and phosphorylates the catalytic alpha subunit of PDHc (PDHA) on two residues S295 and S314, which activates the enzymatic activity of PDHc and alleviates an inhibitory phosphorylation by PDHKs, respectively. Importantly, these phosphorylation events mediate PDHc function in cancer metastasis. Our study reveals that AMPK-mediated PDHA phosphorylation drives PDHc activation and TCA cycle to empower cancer cells adaptation to metastatic microenvironments for metastasis.
    Keywords:  AMPK; PDHA; TCA cycle; breast cancer; cancer metastasis; metabolic stress
    DOI:  https://doi.org/10.1016/j.molcel.2020.09.018
  4. Cell Rep. 2020 Oct 06. pii: S2211-1247(20)31220-1. [Epub ahead of print]33(1): 108231
    Respiratory Supercomplexes Promote Mitochondrial Efficiency and Growth in Severely Hypoxic Pancreatic Cancer.
    Kate E R Hollinshead, Seth J Parker, Vinay V Eapen, Joel Encarnacion-Rosado, Albert Sohn, Tugba Oncu, Michael Cammer, Joseph D Mancias, Alec C Kimmelman.
      Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive fibrosis and hypovascularization, resulting in significant intratumoral hypoxia (low oxygen) that contributes to its aggressiveness, therapeutic resistance, and high mortality. Despite oxygen being a fundamental requirement for many cellular and metabolic processes, and the severity of hypoxia in PDAC, the impact of oxygen deprivation on PDAC biology is poorly understood. Investigating how PDAC cells survive in the near absence of oxygen, we find that PDAC cell lines grow robustly in oxygen tensions down to 0.1%, maintaining mitochondrial morphology, membrane potential, and the oxidative metabolic activity required for the synthesis of key metabolites for proliferation. Disrupting electron transfer efficiency by targeting mitochondrial respiratory supercomplex assembly specifically affects hypoxic PDAC proliferation, metabolism, and in vivo tumor growth. Collectively, our results identify a mechanism that enables PDAC cells to thrive in severe, oxygen-limited microenvironments.
    Keywords:  COX7A2L; aspartate; electron transport chain; hypoxia; pancreatic cancer; respiration; supercomplexes
    DOI:  https://doi.org/10.1016/j.celrep.2020.108231
  5. Cell. 2020 Sep 24. pii: S0092-8674(20)31091-6. [Epub ahead of print]
    Lactate Elicits ER-Mitochondrial Mg2+ Dynamics to Integrate Cellular Metabolism.
    Cassidy C Daw, Karthik Ramachandran, Benjamin T Enslow, Soumya Maity, Brian Bursic, Matthew J Novello, Cherubina S Rubannelsonkumar, Ayah H Mashal, Joel Ravichandran, Terry M Bakewell, Weiwei Wang, Kang Li, Travis R Madaris, Christopher E Shannon, Luke Norton, Soundarya Kandala, Jeffrey Caplan, Subramanya Srikantan, Peter B Stathopulos, W Brian Reeves, Muniswamy Madesh.
      Mg2+ is the most abundant divalent cation in metazoans and an essential cofactor for ATP, nucleic acids, and countless metabolic enzymes. To understand how the spatio-temporal dynamics of intracellular Mg2+ (iMg2+) are integrated into cellular signaling, we implemented a comprehensive screen to discover regulators of iMg2+ dynamics. Lactate emerged as an activator of rapid release of Mg2+ from endoplasmic reticulum (ER) stores, which facilitates mitochondrial Mg2+ (mMg2+) uptake in multiple cell types. We demonstrate that this process is remarkably temperature sensitive and mediated through intracellular but not extracellular signals. The ER-mitochondrial Mg2+ dynamics is selectively stimulated by L-lactate. Further, we show that lactate-mediated mMg2+ entry is facilitated by Mrs2, and point mutations in the intermembrane space loop limits mMg2+ uptake. Intriguingly, suppression of mMg2+ surge alleviates inflammation-induced multi-organ failure. Together, these findings reveal that lactate mobilizes iMg2+ and links the mMg2+ transport machinery with major metabolic feedback circuits and mitochondrial bioenergetics.
    Keywords:  Mrs2; calcium; cancer; channel; endoplasmic reticulum; inflammation; lactate; magnesium; metabolism; mitochondria
    DOI:  https://doi.org/10.1016/j.cell.2020.08.049
  6. Gut. 2020 Oct 07. pii: gutjnl-2020-321217. [Epub ahead of print]
    Multiregion whole-exome sequencing of intraductal papillary mucinous neoplasms reveals frequent somatic KLF4 mutations predominantly in low-grade regions.
    Kohei Fujikura, Waki Hosoda, Matthäus Felsenstein, Qianqian Song, Johannes G Reiter, Lily Zheng, Violeta Beleva Guthrie, Natalia Rincon, Marco Dal Molin, Jonathan Dudley, Joshua D Cohen, Pei Wang, Catherine G Fischer, Alicia M Braxton, Michaël Noë, Martine Jongepier, Carlos Fernández-Del Castillo, Mari Mino-Kenudson, C Max Schmidt, Michele T Yip-Schneider, Rita T Lawlor, Roberto Salvia, Nicholas J Roberts, Elizabeth D Thompson, Rachel Karchin, Anne Marie Lennon, Yuchen Jiao, Laura D Wood.
       OBJECTIVE: Intraductal papillary mucinous neoplasms (IPMNs) are non-invasive precursor lesions that can progress to invasive pancreatic cancer and are classified as low-grade or high-grade based on the morphology of the neoplastic epithelium. We aimed to compare genetic alterations in low-grade and high-grade regions of the same IPMN in order to identify molecular alterations underlying neoplastic progression.
    DESIGN: We performed multiregion whole exome sequencing on tissue samples from 17 IPMNs with both low-grade and high-grade dysplasia (76 IPMN regions, including 49 from low-grade dysplasia and 27 from high-grade dysplasia). We reconstructed the phylogeny for each case, and we assessed mutations in a novel driver gene in an independent cohort of 63 IPMN cyst fluid samples.
    RESULTS: Our multiregion whole exome sequencing identified KLF4, a previously unreported genetic driver of IPMN tumorigenesis, with hotspot mutations in one of two codons identified in >50% of the analyzed IPMNs. Mutations in KLF4 were significantly more prevalent in low-grade regions in our sequenced cases. Phylogenetic analyses of whole exome sequencing data demonstrated diverse patterns of IPMN initiation and progression. Hotspot mutations in KLF4 were also identified in an independent cohort of IPMN cyst fluid samples, again with a significantly higher prevalence in low-grade IPMNs.
    CONCLUSION: Hotspot mutations in KLF4 occur at high prevalence in IPMNs. Unique among pancreatic driver genes, KLF4 mutations are enriched in low-grade IPMNs. These data highlight distinct molecular features of low-grade and high-grade dysplasia and suggest diverse pathways to high-grade dysplasia via the IPMN pathway.
    Keywords:  molecular genetics; mutations; pancreatic cancer; pancreatic pathology; pancreatic tumours
    DOI:  https://doi.org/10.1136/gutjnl-2020-321217
  7. EMBO J. 2020 Oct 06. e101767
    Glycolysis regulates Hedgehog signalling via the plasma membrane potential.
    Stephanie Spannl, Tomasz Buhl, Ioannis Nellas, Salma A Zeidan, K Venkatesan Iyer, Helena Khaliullina, Carsten Schultz, André Nadler, Natalie A Dye, Suzanne Eaton.
      Changes in cell metabolism and plasma membrane potential have been linked to shifts between tissue growth and differentiation, and to developmental patterning. How such changes mediate these effects is poorly understood. Here, we use the developing wing of Drosophila to investigate the interplay between cell metabolism and a key developmental regulator-the Hedgehog (Hh) signalling pathway. We show that reducing glycolysis both lowers steady-state levels of ATP and stabilizes Smoothened (Smo), the 7-pass transmembrane protein that transduces the Hh signal. As a result, the transcription factor Cubitus interruptus accumulates in its full-length, transcription activating form. We show that glycolysis is required to maintain the plasma membrane potential and that plasma membrane depolarization blocks cellular uptake of N-acylethanolamides-lipoprotein-borne Hh pathway inhibitors required for Smo destabilization. Similarly, pharmacological inhibition of glycolysis in mammalian cells induces ciliary translocation of Smo-a key step in pathway activation-in the absence of Hh. Thus, changes in cell metabolism alter Hh signalling through their effects on plasma membrane potential.
    Keywords:  endocannabinoids; glycolysis; hedgehog signalling; metabolism; plasma membrane potential
    DOI:  https://doi.org/10.15252/embj.2019101767
  8. Autophagy. 2020 Oct 04.
    CDKN1B/p27 regulates autophagy via the control of Ragulator and MTOR activity in amino acid-deprived cells.
    Ada Nowosad, Arnaud Besson.
      The tumor suppressor CDKN1B/p27Kip1 binds to and inhibits cyclin-CDK complexes in the nucleus, inducing cell cycle arrest. However, when in the cytoplasm, CDKN1B may promote tumorigenesis. Notably, cytoplasmic CDKN1B was reported to promote macroautophagy/autophagy in response to nutrient shortage by a previously unknown mechanism. In our recent work, we found that during prolonged amino acid starvation, CDKN1B promotes autophagy via an MTORC1-dependent pathway. A fraction of CDKN1B translocates to lysosomes, where it interacts with the Ragulator subunit LAMTOR1, preventing Ragulator assembly, which is required for MTORC1 activation in response to amino acids. Therefore, CDKN1B represses MTORC1 activity, leading to nuclear translocation of the transcription factor TFEB and activation of lysosomal function, enhancing starvation-induced autophagy flux and apoptosis. In contrast, cells lacking CDKN1B survive starvation despite reduced autophagy, due to elevated MTORC1 activation. These findings reveal that, by directly repressing MTORC1 activity, CDKN1B couples the cell cycle and cell growth machineries during metabolic stress.
    DOI:  https://doi.org/10.1080/15548627.2020.1831217
  9. Purinergic Signal. 2020 Oct 06.
    The P2X7 ion channel is dispensable for energy and metabolic homeostasis of white and brown adipose tissues.
    Tian Tian, Markus Heine, Ioannis Evangelakos, Michelle Y Jaeckstein, Nicola Schaltenberg, Tobias Stähler, Friedrich Koch-Nolte, Manju Kumari, Joerg Heeren.
      Several studies suggest a role of extracellular adenine nucleotides in regulating adipose tissue functions via the purinergic signaling network. Metabolic studies in mice with global deletion of the purinergic receptor P2X7 on the C57BL/6 background indicate that this receptor has only a minor role in adipose tissue for diet-induced inflammation or cold-triggered thermogenesis. However, recent data show that a polymorphism (P451L) present in C57BL/6 mice attenuates P2X7 receptor function, whereas BALB/c mice express the fully functional P451 allele. To determine the potential role of P2rx7 under metabolic and thermogenic stress conditions, we performed comparative studies using male P2rx7 knockout (KO) and respective wild-type controls on both BALB/c and C57BL/6 backgrounds. Our data show that adipose P2rx7 mRNA levels are increased in obese mice. Moreover, P2rx7 deficiency results in reduced levels of circulating CCL2 and IL6 with a moderate effect on gene expression of pro-inflammatory markers in white adipose tissue and liver of BALB/c and C57BL/6 mice. However, P2X7 expression does not alter body weight, insulin resistance, and hyperglycemia associated with high-fat diet feeding on both genetic backgrounds. Furthermore, deficiency of P2rx7 is dispensable for energy expenditure at thermoneutral and acute cold exposure conditions. In summary, these data show that-apart from a moderate effect on inflammatory cytokines-P2X7 plays only a minor role in inflammatory and thermogenic effects of white and brown adipose tissue even on the BALB/c background.
    Keywords:  Adipose tissue; Energy metabolism; Obesity; P2X7 ion channel; Purinergic signaling
    DOI:  https://doi.org/10.1007/s11302-020-09738-7
  10. Trends Biochem Sci. 2020 Oct 02. pii: S0968-0004(20)30226-7. [Epub ahead of print]
    Integrins Control Vesicular Trafficking; New Tricks for Old Dogs.
    Martijn A Nolte, Esther N M Nolte-'t Hoen, Coert Margadant.
      Integrins are transmembrane receptors that transduce biochemical and mechanical signals across the plasma membrane and promote cell adhesion and migration. In addition, integrin adhesion complexes are functionally and structurally linked to components of the intracellular trafficking machinery and accumulating data now reveal that they are key regulators of endocytosis and exocytosis in a variety of cell types. Here, we highlight recent insights into integrin control of intracellular trafficking in processes such as degranulation, mechanotransduction, cell-cell communication, antibody production, virus entry, Toll-like receptor signaling, autophagy, and phagocytosis, as well as the release and uptake of extracellular vesicles. We discuss the underlying molecular mechanisms and the implications for a range of pathophysiological contexts, including hemostasis, immunity, tissue repair, cancer, and viral infection.
    Keywords:  clathrin; endocytosis; exocytosis; immunity; integrins; viral infection
    DOI:  https://doi.org/10.1016/j.tibs.2020.09.001
  11. Cancer Metab. 2020 ;8 12
    Modulating pyrimidine ribonucleotide levels for the treatment of cancer.
    Tanzina Mollick, Sonia Laín.
      By providing the necessary building blocks for nucleic acids and precursors for cell membrane synthesis, pyrimidine ribonucleotides are essential for cell growth and proliferation. Therefore, depleting pyrimidine ribonucleotide pools has long been considered as a strategy to reduce cancer cell growth. Here, we review the pharmacological approaches that have been employed to modulate pyrimidine ribonucleotide synthesis and degradation routes and discuss their potential use in cancer therapy. New developments in the treatment of myeloid malignancies with inhibitors of pyrimidine ribonucleotide synthesis justify revisiting the literature as well as discussing whether targeting this metabolic pathway can be effective and sufficiently selective for cancer cells to warrant an acceptable therapeutic index in patients.
    Keywords:  CAD; CDA; CTPS; Cancer therapy; DHODH; Nucleoside transporters; Pyrimidine ribonucleotide metabolism; Therapeutic index; UMPS
    DOI:  https://doi.org/10.1186/s40170-020-00218-5
  12. J Cell Sci. 2020 Oct 08. pii: jcs.248526. [Epub ahead of print]
    Yeast FIT2 homolog is necessary to maintain cellular proteostasis and membrane lipid homeostasis.
    Wei Sheng Yap, Peter Shyu, Maria Laura Gaspar, Stephen A Jesch, Charlie Marvalim, William A Prinz, Susan A Henry, Guillaume Thibault.
      Lipid droplets (LDs) are implicated in conditions of lipid and protein dysregulation. The fat storage inducing transmembrane (FIT) family induces LD formation. Here, we establish a model system to study the role of S. cerevisiae FIT homologues (ScFIT), SCS3 and YFT2, in proteostasis and stress response pathways. While LD biogenesis and basal endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) remain unaltered in ScFIT mutants, SCS3 was found essential for proper stress-induced UPR activation and for viability in the absence of the sole yeast UPR transducer IRE1 Devoid of a functional UPR, muted SCS3 exhibited accumulation of triacylglycerol within the ER along with aberrant LD morphology, suggesting a UPR-dependent compensatory mechanism. Additionally, SCS3 was necessary to maintain phospholipid homeostasis. Strikingly, global protein ubiquitination and the turnover of both ER and cytoplasmic misfolded proteins is impaired in ScFITΔ cells, while a screen for interacting partners of Scs3 identifies components of the proteostatic machinery as putative targets. Together, our data support a model where ScFITs play an important role in lipid metabolism and proteostasis beyond their defined roles in LD biogenesis.
    Keywords:  Endoplasmic reticulum-associated degradation (ERAD); Lipid droplet; Phospholipid metabolism; Proteostasis; Scs3; Unfolded protein response (UPR)
    DOI:  https://doi.org/10.1242/jcs.248526
  13. EMBO Mol Med. 2020 Oct 07. e12010
    FAK activity in cancer-associated fibroblasts is a prognostic marker and a druggable key metastatic player in pancreatic cancer.
    Sonia Zaghdoudi, Emilie Decaup, Ismahane Belhabib, Rémi Samain, Stéphanie Cassant-Sourdy, Julia Rochotte, Alexia Brunel, David Schlaepfer, Jérome Cros, Cindy Neuzillet, Manon Strehaiano, Amandine Alard, Richard Tomasini, Vinothini Rajeeve, Aurélie Perraud, Muriel Mathonnet, Oliver Mt Pearce, Yvan Martineau, Stéphane Pyronnet, Corinne Bousquet, Christine Jean.
      Cancer-associated fibroblasts (CAFs) are considered the most abundant type of stromal cells in pancreatic ductal adenocarcinoma (PDAC), playing a critical role in tumour progression and chemoresistance; however, a druggable target on CAFs has not yet been identified. Here we report that focal adhesion kinase (FAK) activity (evaluated based on 397 tyrosine phosphorylation level) in CAFs is highly increased compared to its activity in fibroblasts from healthy pancreas. Fibroblastic FAK activity is an independent prognostic marker for disease-free and overall survival of PDAC patients (cohort of 120 PDAC samples). Genetic inactivation of FAK within fibroblasts (FAK kinase-dead, KD) reduces fibrosis and immunosuppressive cell number within primary tumours and dramatically decreases tumour spread. FAK pharmacologic or genetic inactivation reduces fibroblast migration/invasion, decreases extracellular matrix (ECM) expression and deposition by CAFs, modifies ECM track generation and negatively impacts M2 macrophage polarization and migration. Thus, FAK activity within CAFs appears as an independent PDAC prognostic marker and a druggable driver of tumour cell invasion.
    Keywords:  cancer-associated fibroblasts; extracellular matrix remodelling; focal adhesion kinase; metastasis; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.15252/emmm.202012010
  14. ACS Omega. 2020 Sep 29. 5(38): 24666-24673
    One-Step High-Throughput Telomerase Activity Measurement of Cell Populations, Single Cells, and Single-Enzyme Complexes.
    Ke-Wei Zheng, Chao Liu, Qing Meng, Yu-Hua Hao, Jin-Ping Zheng, Wei Li, Zheng Tan.
      Telomerase, a key enzyme involved in telomere homeostasis, is a major player involved in or required for sustained cell proliferation. It is expressed in ∼90% tumor but rarely in normal somatic cells. Therefore, telomerase serves as a diagnostic marker and therapeutic target of cancers. Although many methods are available for measuring telomerase activity, a convenient, fast, sensitive, and reliable method is still lacking for routine use in both clinics and research. Here, we present a single-enzyme sensitivity telomere repeat amplification protocol for quantifying telomerase activity. With multiple optimizations, the protocol pushes the ultimate detection limit down to a single telomerase complex, enabling measurement of telomerase activity of not only multiple cancerous/normal cell samples but also single cancer cells alone or even in the presence of 8000 normal cells. Implemented in a one-step mix-and-run format, the protocol offers a most sensitive, fast, accurate, and reproducible quantification of telomerase activity with linearity ranging from 20,000 HeLa cancer cells to a single telomerase complex. It requires minimal manual operation and experimental skill and is convenient for either low or high throughput of samples. We expect that the protocol should provide practical routine analyses of telomerase in both research and clinical applications. As an example, we demonstrate how telomerase activity evolves at the single-cell level and partitions in cell division in early mouse embryo development.
    DOI:  https://doi.org/10.1021/acsomega.0c03246
  15. J Biol Chem. 2020 Oct 06. pii: jbc.RA120.014402. [Epub ahead of print]
    The glucose-sensing transcription factor ChREBP is targeted by proline hydroxylation.
    Steffi Heidenreich, Pamela Weber, Heike Stephanowitz, Konstantin M Petricek, Till Schütte, Moritz Oster, Antti M Salo, Miriam Knauer, Isabel Goehring, Na Yang, Nicole Witte, Anne Schumann, Manuela Sommerfeld, Matthias Muenzner, Johanna Myllyharju, Eberhard Krause, Michael Schupp.
      Cellular energy demands are met by uptake and metabolism of nutrients like glucose. The principal transcriptional regulator for adapting glycolytic flux and downstream pathways like de novo lipogenesis to glucose availability in many cell types is carbohydrate response element binding protein (ChREBP). ChREBP is activated by glucose metabolites and post-translational modifications, inducing nuclear accumulation and regulation of target genes. Here we report that ChREBP is modified by proline hydroxylation at several residues. Proline hydroxylation targets both ectopically expressed ChREBP in cells and endogenous ChREBP in mouse liver. Functionally, we found that specific hydroxylated prolines were dispensable for protein stability but required for the adequate activation of ChREBP upon exposure to high glucose. Accordingly, ChREBP target gene expression was rescued by re-expressing wild-type but not ChREBP that lacks hydroxylated prolines in ChREBP-deleted hepatocytes. Thus, proline hydroxylation of ChREBP is a novel post-translational modification that may allow for therapeutic interference in metabolic diseases.
    Keywords:  carbohydrate function; glucose metabolism; hepatocyte; hydroxyproline; post-translational modification (PTM)
    DOI:  https://doi.org/10.1074/jbc.RA120.014402
  16. Nat Commun. 2020 10 06. 11(1): 5017
    Adaptation and selection shape clonal evolution of tumors during residual disease and recurrence.
    Andrea Walens, Jiaxing Lin, Jeffrey S Damrauer, Brock McKinney, Ryan Lupo, Rachel Newcomb, Douglas B Fox, Nathaniel W Mabe, Jeremy Gresham, Zhecheng Sheng, Alexander B Sibley, Tristan De Buysscher, Hemant Kelkar, Piotr A Mieczkowski, Kouros Owzar, James V Alvarez.
      The survival and recurrence of residual tumor cells following therapy constitutes one of the biggest obstacles to obtaining cures in breast cancer, but it remains unclear how the clonal composition of tumors changes during relapse. We use cellular barcoding to monitor clonal dynamics during tumor recurrence in vivo. We find that clonal diversity decreases during tumor regression, residual disease, and recurrence. The recurrence of dormant residual cells follows several distinct routes. Approximately half of the recurrent tumors exhibit clonal dominance with a small number of subclones comprising the vast majority of the tumor; these clonal recurrences are frequently dependent upon Met gene amplification. A second group of recurrent tumors comprises thousands of subclones, has a clonal architecture similar to primary tumors, and is dependent upon the Jak/Stat pathway. Thus the regrowth of dormant tumors proceeds via multiple routes, producing recurrent tumors with distinct clonal composition, genetic alterations, and drug sensitivities.
    DOI:  https://doi.org/10.1038/s41467-020-18730-z
  17. Nat Commun. 2020 Oct 09. 11(1): 5120
    Concepts of extracellular matrix remodelling in tumour progression and metastasis.
    Juliane Winkler, Abisola Abisoye-Ogunniyan, Kevin J Metcalf, Zena Werb.
      Tissues are dynamically shaped by bidirectional communication between resident cells and the extracellular matrix (ECM) through cell-matrix interactions and ECM remodelling. Tumours leverage ECM remodelling to create a microenvironment that promotes tumourigenesis and metastasis. In this review, we focus on how tumour and tumour-associated stromal cells deposit, biochemically and biophysically modify, and degrade tumour-associated ECM. These tumour-driven changes support tumour growth, increase migration of tumour cells, and remodel the ECM in distant organs to allow for metastatic progression. A better understanding of the underlying mechanisms of tumourigenic ECM remodelling is crucial for developing therapeutic treatments for patients.
    DOI:  https://doi.org/10.1038/s41467-020-18794-x
  18. Sci Signal. 2020 Oct 06. pii: eaax4585. [Epub ahead of print]13(652):
    Breast cancer-associated macrophages promote tumorigenesis by suppressing succinate dehydrogenase in tumor cells.
    Valentí Gómez, Thomas R Eykyn, Rami Mustapha, Fabián Flores-Borja, Victoria Male, Paul R Barber, Antonia Patsialou, Ryan Green, Fani Panagaki, Chun W Li, Gilbert O Fruhwirth, Susana Ros, Kevin M Brindle, Tony Ng.
      Tumor-associated macrophages (TAMs) can exist in pro- and anti-inflammatory states. Anti-inflammatory TAMs (also referred to as M2-polarized) generally suppress antitumor immune responses and enhance the metastatic progression of cancer. To explore the mechanisms behind this phenomenon, we isolated macrophages from mice and humans, polarized them ex vivo, and examined their functional interaction with breast cancer cells in culture and in mice. We found that anti-inflammatory TAMs promoted a metabolic state in breast cancer cells that supported various protumorigenic phenotypes. Anti-inflammatory TAMs secreted the cytokine TGF-β that, upon engagement of its receptors in breast cancer cells, suppressed the abundance of the transcription factor STAT1 and, consequently, decreased that of the metabolic enzyme succinate dehydrogenase (SDH) in the tumor cells. The decrease in SDH levels in tumor cells resulted in an accumulation of succinate, which enhanced the stability of the transcription factor HIF1α and reprogrammed cell metabolism to a glycolytic state. TAM depletion-repletion experiments in a 4T1 mouse model additionally revealed that anti-inflammatory macrophages promoted HIF-associated vascularization and expression of the immunosuppressive protein PD-L1 in tumors. The findings suggest that anti-inflammatory TAMs promote tumor-associated angiogenesis and immunosuppression by altering metabolism in breast cancer cells.
    DOI:  https://doi.org/10.1126/scisignal.aax4585
  19. Aging (Albany NY). 2020 Oct 06. 12
    Reduced mitochondrial translation prevents diet-induced metabolic dysfunction but not inflammation.
    Kara L Perks, Nicola Ferreira, Judith A Ermer, Danielle L Rudler, Tara R Richman, Giulia Rossetti, Vance B Matthews, Natalie C Ward, Oliver Rackham, Aleksandra Filipovska.
      The contribution of dysregulated mitochondrial gene expression and consequent imbalance in biogenesis is not well understood in metabolic disorders such as insulin resistance and obesity. The ribosomal RNA maturation protein PTCD1 is essential for mitochondrial protein synthesis and its reduction causes adult-onset obesity and liver steatosis. We used haploinsufficient Ptcd1 mice fed normal or high fat diets to understand how changes in mitochondrial biogenesis can lead to metabolic dysfunction. We show that Akt-stimulated reduction in lipid content and upregulation of mitochondrial biogenesis effectively protected mice with reduced mitochondrial protein synthesis from excessive weight gain on a high fat diet, resulting in improved glucose and insulin tolerance and reduced lipid accumulation in the liver. However, inflammation of the white adipose tissue and early signs of fibrosis in skeletal muscle, as a consequence of reduced protein synthesis, were exacerbated with the high fat diet. We identify that reduced mitochondrial protein synthesis and OXPHOS biogenesis can be recovered in a tissue-specific manner via Akt-mediated increase in insulin sensitivity and transcriptional activation of the mitochondrial stress response.
    Keywords:  mTOR and insulin signaling pathways; metabolic syndrome; mitochondria; obesity; stress response
    DOI:  https://doi.org/10.18632/aging.104010
  20. Annu Rev Cell Dev Biol. 2020 Oct 06. 36 115-139
    Protein Quality Control and Lipid Droplet Metabolism.
    Melissa A Roberts, James A Olzmann.
      Lipid droplets (LDs) are endoplasmic reticulum-derived organelles that consist of a core of neutral lipids encircled by a phospholipid monolayer decorated with proteins. As hubs of cellular lipid and energy metabolism, LDs are inherently involved in the etiology of prevalent metabolic diseases such as obesity and nonalcoholic fatty liver disease. The functions of LDs are regulated by a unique set of associated proteins, the LD proteome, which includes integral membrane and peripheral proteins. These proteins control key activities of LDs such as triacylglycerol synthesis and breakdown, nutrient sensing and signal integration, and interactions with other organelles. Here we review the mechanisms that regulate the composition of the LD proteome, such as pathways that mediate selective and bulk LD protein degradation and potential connections between LDs and cellular protein quality control.
    Keywords:  chaperone-mediated autophagy; endoplasmic reticulum; lipid droplet; lipophagy; metabolism; proteasome; protein targeting; triacylglycerol; ubiquitin
    DOI:  https://doi.org/10.1146/annurev-cellbio-031320-101827
  21. Clin Cancer Res. 2020 Oct 07. pii: clincanres.1788.2020. [Epub ahead of print]
    Effect of germline mutations in homologous recombination repair genes on overall survival of patients with pancreatic adenocarcinoma.
    Siddhartha Yadav, Pashtoon Murtaza Kasi, William R Bamlet, Thanh P Ho, Eric C Polley, Chunling Hu, Steven N Hart, Kari G Rabe, Nicholas J Boddicker, Rohan D Gnanaolivu, Kun Y Lee, Tricia Lindstrom, Gloria M Petersen, Fergus J Couch, Robert R McWilliams.
       PURPOSE: To compare the clinical characteristics and overall survival (OS) of germline mutation carriers in homologous recombination repair (HRR) genes and non-carriers with pancreatic ductal adenocarcinoma (PDAC).
    METHODS: Germline DNA from 3,078 patients with PDAC enrolled in a prospective registry at Mayo Clinic between 2000 and 2017 was analyzed for mutations in 37 cancer predisposition genes. Characteristics and OS of patients with mutations in 8 genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, PALB2, RAD51C, and RAD51D) involved in HRR were compared to patients testing negative for mutations in all 37 genes.
    RESULTS: The 175 HRR mutation carriers and 2,730 non-carriers in the study had a median duration of follow-up of 9.9 years. HRR mutation carriers were younger (Median age at diagnosis: 63 vs. 66 years, p<0.001) and more likely to have metastatic disease at diagnosis (46% vs. 36%, p=0.004). In a multivariable model adjusting for sex, age at diagnosis, and tumor staging, patients with germline HRR mutations had a significantly longer OS compared to non-carriers (HR: 0.83, 95% CI: 0.70 to 0.97, p= 0.02). Further gene-level analysis demonstrated that germline ATM mutation carriers had longer OS compared to patients without germline mutations in any of the 37 HRR genes (HR: 0.72, 95% CI: 0.55 - 0.94, p=0.01).
    CONCLUSIONS: This study demonstrates that germline mutation carrier status in PDAC is associated with longer OS compared to non-carriers. Further research into tumor biology and response to platinum-based chemotherapy in germline mutation carriers with PDAC are needed to better understand the association with longer OS.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-20-1788
  22. Mol Cancer Ther. 2020 Oct 09. pii: molcanther.0911.2019. [Epub ahead of print]
    Heat shock protein-90 inhibition alters activation of pancreatic stellate cells and enhances the efficacy of PD-1 blockade in pancreatic cancer.
    Gregory B Lesinski, Yuchen Zhang, Michael B Ware, Mohammad Y Zaidi, Amanda N Ruggieri, Brian M Olson, Hannah Komar, Matthew R Farren, Ganji Purnachandra Nagaraju, Chao Zhang, Zhengjia Chen, Juan M Sarmiento, Rafi Ahmed, Shishir K Maithel, Bassel F El-Rayes.
      Pancreatic ductal adenocarcinoma (PDAC) has a prominent fibrotic stroma, which is a result of interactions between tumor, immune and pancreatic stellate cells (PSC) or cancer associated fibroblasts (CAF). Targeting inflammatory pathways present within the stroma may improve access of effector immune cells to PDAC and response to immunotherapy. Heat shock protein-90 (Hsp90), is a chaperone protein and a versatile target in pancreatic cancer. Hsp90 regulates a diverse array of cellular processes of relevance to both the tumor and the immune system. However, to date the role of Hsp90 in PSC/CAF has not been explored in detail. We hypothesized that Hsp90 inhibition would limit inflammatory signals, thereby reprogramming the PDAC tumor microenvironment to enhance sensitivity to PD-1 blockade. Treatment of immortalized and primary patient PSC/CAF with the Hsp90 inhibitor XL888 decreased IL-6, a key cytokine that orchestrates immune changes in PDAC at the transcript and protein level in vitro. XL888 directly limited PSC/CAF growth, and reduced Jak/STAT and MAPK signaling intermediates and alpha-SMA expression as determined via immunoblot. Combined therapy with XL888 and anti-PD-1 was efficacious in C57BL/6 mice bearing syngeneic subcutaneous (Panc02) or orthotopic (KPC Luc) tumors. Tumors from mice treated with both XL888 and anti-PD-1 had a significantly increased CD8+ and CD4+ T cell infiltrate and a unique transcriptional profile characterized by upregulation of genes associated with immune response and chemotaxis. These data demonstrate that Hsp90 inhibition directly impacts PSC/CAF in vitro and enhances the efficacy of anti-PD-1 blockade in vivo.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-19-0911
  23. Nat Commun. 2020 10 07. 11(1): 5052
    Autophagy facilitates adaptation of budding yeast to respiratory growth by recycling serine for one-carbon metabolism.
    Alexander I May, Mark Prescott, Yoshinori Ohsumi.
      The mechanism and function of autophagy as a highly-conserved bulk degradation pathway are well studied, but the physiological role of autophagy remains poorly understood. We show that autophagy is involved in the adaptation of Saccharomyces cerevisiae to respiratory growth through its recycling of serine. On respiratory media, growth onset, mitochondrial initiator tRNA modification and mitochondrial protein expression are delayed in autophagy defective cells, suggesting that mitochondrial one-carbon metabolism is perturbed in these cells. The supplementation of serine, which is a key one-carbon metabolite, is able to restore mitochondrial protein expression and alleviate delayed respiratory growth. These results indicate that autophagy-derived serine feeds into mitochondrial one-carbon metabolism, supporting the initiation of mitochondrial protein synthesis and allowing rapid adaptation to respiratory growth.
    DOI:  https://doi.org/10.1038/s41467-020-18805-x
  24. Nat Med. 2020 Oct 05.
    Clinical utility of circulating tumor DNA sequencing in advanced gastrointestinal cancer: SCRUM-Japan GI-SCREEN and GOZILA studies.
    Yoshiaki Nakamura, Hiroya Taniguchi, Masafumi Ikeda, Hideaki Bando, Ken Kato, Chigusa Morizane, Taito Esaki, Yoshito Komatsu, Yasuyuki Kawamoto, Naoki Takahashi, Makoto Ueno, Yoshinori Kagawa, Tomohiro Nishina, Takeshi Kato, Yoshiyuki Yamamoto, Junji Furuse, Tadamichi Denda, Hisato Kawakami, Eiji Oki, Takako Nakajima, Naohiro Nishida, Kensei Yamaguchi, Hisateru Yasui, Masahiro Goto, Nobuhisa Matsuhashi, Koushiro Ohtsubo, Kentaro Yamazaki, Akihito Tsuji, Wataru Okamoto, Katsuya Tsuchihara, Takeharu Yamanaka, Izumi Miki, Yasutoshi Sakamoto, Hiroko Ichiki, Masayuki Hata, Riu Yamashita, Atsushi Ohtsu, Justin I Odegaard, Takayuki Yoshino.
      Comprehensive genomic profiling enables genomic biomarker detection in advanced solid tumors. Here, to evaluate the utility of circulating tumor DNA (ctDNA) genotyping, we compare trial enrollment using ctDNA sequencing in 1,687 patients with advanced gastrointestinal (GI) cancer in SCRUM-Japan GOZILA (no. UMIN000016343), an observational ctDNA-based screening study, to enrollment using tumor tissue sequencing in the same centers and network (GI-SCREEN, 5,621 patients). ctDNA genotyping significantly shortened the screening duration (11 versus 33 days, P < 0.0001) and improved the trial enrollment rate (9.5 versus 4.1%, P < 0.0001) without compromising treatment efficacy compared to tissue genotyping. We also describe the clonal architecture of ctDNA profiles in ~2,000 patients with advanced GI cancer, which reinforces the relevance of many targetable oncogenic drivers and highlights multiple new drivers as candidates for clinical development. ctDNA genotyping has the potential to accelerate innovation in precision medicine and its delivery to individual patients.
    DOI:  https://doi.org/10.1038/s41591-020-1063-5
  25. Cell. 2020 Oct 03. pii: S0092-8674(20)31161-2. [Epub ahead of print]
    TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS.
    Chien-Hsiung Yu, Sophia Davidson, Cassandra R Harapas, James B Hilton, Michael J Mlodzianoski, Pawat Laohamonthonkul, Cynthia Louis, Ronnie Ren Jie Low, Jonas Moecking, Dominic De Nardo, Katherine R Balka, Dale J Calleja, Fiona Moghaddas, Erya Ni, Catriona A McLean, Andre L Samson, Shiraz Tyebji, Christopher J Tonkin, Christopher R Bye, Bradley J Turner, Genevieve Pepin, Michael P Gantier, Kelly L Rogers, Kate McArthur, Peter J Crouch, Seth L Masters.
      Cytoplasmic accumulation of TDP-43 is a disease hallmark for many cases of amyotrophic lateral sclerosis (ALS), associated with a neuroinflammatory cytokine profile related to upregulation of nuclear factor κB (NF-κB) and type I interferon (IFN) pathways. Here we show that this inflammation is driven by the cytoplasmic DNA sensor cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) when TDP-43 invades mitochondria and releases DNA via the permeability transition pore. Pharmacologic inhibition or genetic deletion of cGAS and its downstream signaling partner STING prevents upregulation of NF-κB and type I IFN induced by TDP-43 in induced pluripotent stem cell (iPSC)-derived motor neurons and in TDP-43 mutant mice. Finally, we document elevated levels of the specific cGAS signaling metabolite cGAMP in spinal cord samples from patients, which may be a biomarker of mtDNA release and cGAS/STING activation in ALS. Our results identify mtDNA release and cGAS/STING activation as critical determinants of TDP-43-associated pathology and demonstrate the potential for targeting this pathway in ALS.
    Keywords:  ALS; IFN; NF-κB; STING; TDP-43; cGAMP; cGAS; mPTP; mitochondria; neurodegeneration
    DOI:  https://doi.org/10.1016/j.cell.2020.09.020
  26. Cell Cycle. 2020 Oct 04. 1-9
    Mapping metabolic oscillations during cell cycle progression.
    Irena Roci, Jeramie D Watrous, Kim A Lagerborg, Mohit Jain, Roland Nilsson.
      Proliferating cells must synthesize a wide variety of macromolecules while progressing through the cell cycle, but the coordination between cell cycle progression and cellular metabolism is still poorly understood. To identify metabolic processes that oscillate over the cell cycle, we performed comprehensive, non-targeted liquid chromatography-high resolution mass spectrometry (LC-HRMS) based metabolomics of HeLa cells isolated in the G1 and SG2M cell cycle phases, capturing thousands of diverse metabolite ions. When accounting for increased total metabolite abundance due to cell growth throughout the cell cycle, 18% of the observed LC-HRMS peaks were at least twofold different between the stages, consistent with broad metabolic remodeling throughout the cell cycle. While most amino acids, phospholipids, and total ribonucleotides were constant across cell cycle phases, consistent with the view that total macromolecule synthesis does not vary across the cell cycle, certain metabolites were oscillating. For example, ribonucleotides were highly phosphorylated in SG2M, indicating an increase in energy charge, and several phosphatidylinositols were more abundant in G1, possibly indicating altered membrane lipid signaling. Within carbohydrate metabolism, pentose phosphates and methylglyoxal metabolites were associated with the cycle. Interestingly, hundreds of yet uncharacterized metabolites similarly oscillated between cell cycle phases, suggesting previously unknown metabolic activities that may be synchronized with cell cycle progression, providing an important resource for future studies.
    Keywords:  Metabolomics; S-lactoylglutathione; cell sorting
    DOI:  https://doi.org/10.1080/15384101.2020.1825203
  27. Proc Natl Acad Sci U S A. 2020 Oct 05. pii: 202009495. [Epub ahead of print]
    Mechanoactivation of NOX2-generated ROS elicits persistent TRPM8 Ca2+ signals that are inhibited by oncogenic KRas.
    Stephen J P Pratt, Rachel M Lee, Katarina T Chang, Erick O Hernández-Ochoa, David A Annis, Eleanor C Ory, Keyata N Thompson, Patrick C Bailey, Trevor J Mathias, Julia A Ju, Michele I Vitolo, Martin F Schneider, Joseph P Stains, Christopher W Ward, Stuart S Martin.
      Changes in the mechanical microenvironment and mechanical signals are observed during tumor progression, malignant transformation, and metastasis. In this context, understanding the molecular details of mechanotransduction signaling may provide unique therapeutic targets. Here, we report that normal breast epithelial cells are mechanically sensitive, responding to transient mechanical stimuli through a two-part calcium signaling mechanism. We observed an immediate, robust rise in intracellular calcium (within seconds) followed by a persistent extracellular calcium influx (up to 30 min). This persistent calcium was sustained via microtubule-dependent mechanoactivation of NADPH oxidase 2 (NOX2)-generated reactive oxygen species (ROS), which acted on transient receptor potential cation channel subfamily M member 8 (TRPM8) channels to prolong calcium signaling. In contrast, the introduction of a constitutively active oncogenic KRas mutation inhibited the magnitude of initial calcium signaling and severely blunted persistent calcium influx. The identification that oncogenic KRas suppresses mechanically-induced calcium at the level of ROS provides a mechanism for how KRas could alter cell responses to tumor microenvironment mechanics and may reveal chemotherapeutic targets for cancer. Moreover, we find that expression changes in both NOX2 and TRPM8 mRNA predict poor clinical outcome in estrogen receptor (ER)-negative breast cancer patients, a population with limited available treatment options. The clinical and mechanistic data demonstrating disruption of this mechanically-activated calcium pathway in breast cancer patients and by KRas activation reveal signaling alterations that could influence cancer cell responses to the tumor mechanical microenvironment and impact patient survival.
    Keywords:  X-ROS; detyrosination; breast cancer; calcium; mechanotransduction
    DOI:  https://doi.org/10.1073/pnas.2009495117
  28. Trends Cell Biol. 2020 Oct 06. pii: S0962-8924(20)30171-9. [Epub ahead of print]
    When Endoplasmic Reticulum Proteostasis Meets the DNA Damage Response.
    Matías González-Quiroz, Alice Blondel, Alfredo Sagredo, Claudio Hetz, Eric Chevet, Rémy Pedeux.
      Sustaining both proteome and genome integrity (GI) requires the integration of a wide range of mechanisms and signaling pathways. These comprise, in particular, the unfolded protein response (UPR) and the DNA damage response (DDR). These adaptive mechanisms take place respectively in the endoplasmic reticulum (ER) and in the nucleus. UPR and DDR alterations are associated with aging and with pathologies such as degenerative diseases, metabolic and inflammatory disorders, and cancer. We discuss the emerging signaling crosstalk between UPR stress sensors and the DDR, as well as their involvement in cancer biology.
    Keywords:  ATM; DNA damage response; IRE1α; PERK; proteostasis; unfolded protein response
    DOI:  https://doi.org/10.1016/j.tcb.2020.09.002
  29. J Clin Invest. 2020 Oct 08. pii: 138315. [Epub ahead of print]
    Mutant SF3B1 promotes AKT and NF-kB driven mammary tumorigenesis.
    Bo Liu, Zhaoqi Liu, Sisi Chen, Michelle Ki, Caroline Erickson, Jorge S Reis-Filho, Benjamin H Durham, Qing Chang, Elisa de Stanchina, Yiwei Sun, Raul Rabadan, Omar Abdel-Wahab, Sarat Chandarlapaty.
      Mutations in the core RNA splicing factor SF3B1 are prevalent in leukemias and uveal melanoma but hotspot SF3B1 mutations are also seen in epithelial malignancies such as breast cancer. Although hotspot mutations in SF3B1 alter hematopoietic differentiation, whether SF3B1 mutations contribute to epithelial cancer development and progression is unknown. Here, we identify that SF3B1 mutations in mammary epithelial and breast cancer cells induce a recurrent pattern of aberrant splicing leading to activation of AKT and NF-kB, enhanced cell migration, and accelerated tumorigenesis. Transcriptomic analysis of human cancer specimens, MMTV-cre Sf3b1K700E/WT mice, and isogenic mutant cell lines identified hundreds of aberrant 3' splice sites (3'ss) induced by mutant SF3B1. Consistently between mouse and human tumors, mutant SF3B1 promoted aberrant splicing (dependent on aberrant branchpoints as well as pyrimidines downstream of the cryptic 3'ss) and consequent suppression of PPP2R5A and MAP3K7, critical negative regulators of AKT and NF-kB. Coordinate activation of NF-kB and AKT signaling was observed in the knock-in models, leading to accelerated cell migration and tumor development in combination with mutant PIK3CA but also hypersensitizing cells to AKT kinase inhibitors. These data identify hotspot mutations in SF3B1 as an important contributor to breast tumorigenesis and reveal unique vulnerabilities in cancers harboring them.
    Keywords:  Breast cancer; Oncology; RNA processing
    DOI:  https://doi.org/10.1172/JCI138315
  30. Mol Biol Cell. 2020 Oct 07. mbcE20020127
    RAC1 induces nuclear alterations through the LINC complex to enhance melanoma invasiveness.
    Paula Colón-Bolea, Rocío García -Gómez, Sue Shackleton, Piero Crespo, Xosé R Bustelo, Berta Casar.
      RHO GTPases are key regulators of the cytoskeletal architecture, which impacts on a broad range of biological processes in malignant cells including motility, invasion and metastasis, thereby affecting tumor progression. One of the constrains during cell migration, is the diameter of the pores through which cells pass. In this respect, the size and shape of the nucleus poses a major limitation. Therefore, enhanced nuclear plasticity can promote cell migration. Nuclear morphology is determined in part through the cytoskeleton, which connects to the nucleoskeleton through the LINC complex. Here, we unravel the role of RAC1 as an orchestrator of nuclear morphology in melanoma cells. We demonstrate that activated RAC1 promotes nuclear alterations through its effector PAK1 and the tubulin cytoskeleton, thereby enhancing migration and intravasation of melanoma cells. Disruption of the LINC complex prevented RAC1-induced nuclear alterations and the invasive properties of melanoma cells. Thus, RAC1 induces nuclear morphology alterations through microtubules and the LINC complex to promote an invasive phenotype in melanoma cells. [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E20-02-0127
  31. Ageing Res Rev. 2020 Oct 05. pii: S1568-1637(20)30323-8. [Epub ahead of print] 101188
    Targeting metabolic pathways for extension of lifespan and healthspan across multiple species.
    Andrey A Parkhitko, Elizabeth Filine, Stephanie E Mohr, Alexey Moskalev, Norbert Perrimon.
      Metabolism plays a significant role in the regulation of aging at different levels, and metabolic reprogramming represents a major driving force in aging. Metabolic reprogramming leads to impaired organismal fitness, an age-dependent increase in susceptibility to diseases, decreased ability to mount a stress response, and increased frailty. The complexity of age-dependent metabolic reprogramming comes from the multitude of levels on which metabolic changes can be connected to aging and regulation of lifespan. This is further complicated by the different metabolic requirements of various tissues, cross-organ communication via metabolite secretion, and direct effects of metabolites on epigenetic state and redox regulation; however, not all of these changes are causative to aging. Studies in yeast, flies, worms, and mice have played a crucial role in identifying mechanistic links between observed changes in various metabolic traits and their effects on lifespan. Here, we review how changes in the organismal and organ-specific metabolome are associated with aging and how targeting of any one of over a hundred different targets in specific metabolic pathways can extend lifespan. An important corollary is that restriction or supplementation of different metabolites can change activity of these metabolic pathways in ways that improve healthspan and extend lifespan in different organisms. Due to the high levels of conservation of metabolism in general, translating findings from model systems to human beings will allow for the development of effective strategies for human health- and lifespan extension.
    Keywords:  Aging; C. elegans; Drosophila; Metabolism; Mice; Yeast
    DOI:  https://doi.org/10.1016/j.arr.2020.101188
  32. Elife. 2020 Oct 07. pii: e59442. [Epub ahead of print]9
    Collagen-rich omentum is a premetastatic niche for integrin α2-mediated peritoneal metastasis.
    Yen-Lin Huang, Ching-Yeu Liang, Danilo Ritz, Ricardo Coelho, Dedy Septiadi, Manuela Estermann, Cécile Cumin, Natalie Rimmer, Andreas Schötzau, Mónica Núñez López, André Fedier, Martina Konantz, Tatjana Vlajnic, Diego Calabrese, Claudia Lengerke, Leonor David, Barbara Rothen-Rutishauser, Francis Jacob, Viola Heinzelmann-Schwarz.
      The extracellular matrix (ECM) plays critical roles in tumor progression and metastasis. However, the contribution of ECM proteins to early metastatic onset in the peritoneal cavity remains unexplored. Here, we suggest a new route of metastasis through the interaction of integrin alpha 2 (ITGA2) with collagens enriched in the tumor coinciding with poor outcome in patients with ovarian cancer. Using multiple gene-edited cell lines and patient-derived samples, we demonstrate that ITGA2 triggers cancer cell adhesion to collagen, promotes cell migration, anoikis resistance, mesothelial clearance, and peritoneal metastasis in vitro and in vivo. Mechanistically, phosphoproteomics identify an ITGA2-dependent phosphorylation of focal adhesion kinase and mitogen-activated protein kinase pathway leading to enhanced oncogenic properties. Consequently, specific inhibition of ITGA2-mediated cancer cell-collagen interaction or targeting focal adhesion signaling may present an opportunity for therapeutic intervention of metastatic spread in ovarian cancer.
    Keywords:  Cell adhesion; Collagen; Peritoneal metastasis; cancer biology; cell biology; focal adhesion kinase; human; integrin alpah 2; mouse; omentum; zebrafish
    DOI:  https://doi.org/10.7554/eLife.59442
  33. Cell Metab. 2020 Sep 29. pii: S1550-4131(20)30491-5. [Epub ahead of print]
    Immunometabolism in the Single-Cell Era.
    Maxim N Artyomov, Jan Van den Bossche.
      Emerging research has identified metabolic pathways that are crucial for the proper regulation of immune cells and how, when deranged, they can cause immune dysfunction and disease progression. However, due to technical limitations such insights have relied heavily on bulk measurements in immune cells, often activated in vitro. But with the emergence of single-cell applications, researchers can now estimate the metabolic state of individual immune cells in clinical samples. Here, we review these single-cell techniques and their ability to validate common principles in immunometabolism, while also revealing context-dependent metabolic heterogeneity within the immune cell compartment. We also discuss current gaps and limitations, as well as identify future opportunities to move the field forward toward the development of therapeutic targets and improved diagnostic capabilities.
    Keywords:  ▪▪▪
    DOI:  https://doi.org/10.1016/j.cmet.2020.09.013
  34. Sci Adv. 2020 Oct;pii: eaaz9124. [Epub ahead of print]6(41):
    A 3D atlas of the dynamic and regional variation of pancreatic innervation in diabetes.
    Alexandra Alvarsson, Maria Jimenez-Gonzalez, Rosemary Li, Carolina Rosselot, Nikolaos Tzavaras, Zhuhao Wu, Andrew F Stewart, Adolfo Garcia-Ocaña, Sarah A Stanley.
      Understanding the detailed anatomy of the endocrine pancreas, its innervation, and the remodeling that occurs in diabetes can provide new insights into metabolic disease. Using tissue clearing and whole-organ imaging, we identified the 3D associations between islets and innervation. This technique provided detailed quantification of α and β cell volumes and pancreatic nerve fibers, their distribution and heterogeneity in healthy tissue, canonical mouse models of diabetes, and samples from normal and diabetic human pancreata. Innervation was highly enriched in the mouse endocrine pancreas, with regional differences. Islet nerve density was increased in nonobese diabetic mice, in mice treated with streptozotocin, and in pancreata of human donors with type 2 diabetes. Nerve contacts with β cells were preserved in diabetic mice and humans. In summary, our whole-organ assessment allows comprehensive examination of islet characteristics and their innervation and reveals dynamic regulation of islet innervation in diabetes.
    DOI:  https://doi.org/10.1126/sciadv.aaz9124
  35. J Cancer. 2020 ;11(21): 6299-6318
    Development and validation of a metastasis-related Gene Signature for predicting the Overall Survival in patients with Pancreatic Ductal Adenocarcinoma.
    Mengwei Wu, Xiaobin Li, Rui Liu, Hongwei Yuan, Wei Liu, Ziwen Liu.
      Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal, aggressive cancer characterized by invasiveness and metastasis. In this study, we aimed to propose a gene prediction model based on metastasis-related genes (MTGs) to more accurately predict PDAC prognosis. Methods: Differentially expressed MTGs (DE-MTGs) were identified via integrated analysis of gene expression omnibus (GEO) datasets and Human Cancer Metastasis Database (HCMDB). Overall survival (OS) related DE-MTGs were then identified and a prognostic gene signature was established using Lasso-Cox regression with TCGA-PAAD datasets. Tumor immunity was analyzed using ESTIMATE and CIBERSORT algorithms. Finally, a nomogram predicting 1-year, 2-year, and 3-year OS of PDAC patients was established based on the prognostic gene signature and relevant clinical parameters using a stepwise Cox regression model. Results: A total of 36 DE-MTGs related to OS were identified in PDAC. Consequently, an MTG-based gene signature comprising of RACGAP1, RARRES3, TPX2, MMP28, GPR87, KIF14, and TSPAN7 was established to predict the OS of PDAC. The MTG-based gene signature was able to distinguish high-risk patients with significantly poorer prognosis and accurately predict OS of PDAC in both the training and external validation datasets. Cox regression analysis indicated that the MTG-based gene signature was an independent prognostic factor in PDAC. The gene set enrichment analysis (GSEA) showed that molecular alterations in the high-risk group were associated with multiple oncological pathways. Moreover, analysis of tumor immunity revealed significantly higher levels of follicular helper T cells and M0 macrophage infiltration, and lower levels of infiltrating naïve B cells, CD8 T cells, monocytes, and resting dendritic cells in the high-risk group. Immune cell infiltration levels were significantly associated with the expression of the seven DE-MTGs. Finally, a nomogram was established by incorporating the prognostic gene signature and clinical parameters, which was superior to the AJCC staging system in predicting the OS of PDAC patients. Conclusions: The DE-MTGs we identified were closely associated with the progress and prognosis of PDAC and are potential therapeutic targets. The MTG-based gene signature and nomogram may serve to improve the individualized prediction of survival, assisting in clinical decision-making.
    Keywords:  Gene Expression Omnibus; The Cancer Genome Atlas Program; nomogram; overall survival; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.7150/jca.47629
  36. Trends Neurosci. 2020 Sep 30. pii: S0166-2236(20)30192-2. [Epub ahead of print]
    Walking with Salamanders: From Molecules to Biorobotics.
    Dimitri Ryczko, András Simon, Auke Jan Ijspeert.
      How do four-legged animals adapt their locomotion to the environment? How do central and peripheral mechanisms interact within the spinal cord to produce adaptive locomotion and how is locomotion recovered when spinal circuits are perturbed? Salamanders are the only tetrapods that regenerate voluntary locomotion after full spinal transection. Given their evolutionary position, they provide a unique opportunity to bridge discoveries made in fish and mammalian models. Genetic dissection of salamander neural circuits is becoming feasible with new methods for precise manipulation, elimination, and visualisation of cells. These approaches can be combined with classical tools in neuroscience and with modelling and a robotic environment. We propose that salamanders provide a blueprint of the function, evolution, and regeneration of tetrapod locomotor circuits.
    Keywords:  genome editing; locomotion; neuronal network; numerical modelling; regeneration; robotics; salamander
    DOI:  https://doi.org/10.1016/j.tins.2020.08.006
  37. Cancer Res. 2020 Oct 06. pii: canres.1956.2020. [Epub ahead of print]
    Field carcinogenesis in cancer evolution: what the cell is going on?
    Ansam Sinjab, Guangchun Han, Linghua Wang, Humam Kadara.
      Field carcinogenesis describes the prevalence of tumor-related alterations in normal-appearing tissues. Here we summarize recent efforts in profiling field molecular dynamics for resolving early events in cancer evolution. We also highlight gaps in our knowledge of the molecular and cellular heterogeneity of field carcinogenesis and propose directions to tackle these voids using single cell-based approaches and unique tissue sampling models. By interrogating both the mutagenized epithelium and its microenvironment, we surmise that single cell-guided studies will help chart the spatiotemporal molecular and cellular "atlas" of field carcinogenesis, will further delineate preneoplastic initiation and progression, and will help identify cancer prevention and early intervention targets.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-1956
  38. Elife. 2020 Oct 07. pii: e60225. [Epub ahead of print]9
    RUNX1 marks a luminal castration resistant lineage established at the onset of prostate development.
    Renaud Mevel, Ivana Steiner, Susan Mason, Laura Ca Galbraith, Rahima Patel, Muhammad Zh Fadlullah, Imran Ahmad, Hing Y Leung, Pedro Oliveira, Karen Blyth, Esther Baena, Georges Lacaud.
      The characterization of prostate epithelial hierarchy and lineage heterogeneity is critical to understand its regenerative properties and malignancies. Here, we report that the transcription factor RUNX1 marks a specific subpopulation of proximal luminal cells (PLCs), enriched in the periurethral region of the developing and adult mouse prostate, and distinct from the previously identified NKX3.1+ luminal castration resistant cells. Using scRNA-seq profiling and genetic lineage tracing, we show that RUNX1+ PLCs are unaffected by androgen deprivation, and do not contribute to the regeneration of the distal luminal compartments. Furthermore, we demonstrate that a transcriptionally similar RUNX1+ population emerges at the onset of embryonic prostate specification to populate the proximal region of the ducts. Collectively, our results reveal that RUNX1+ PLCs is an intrinsic castration-resistant and self-sustained lineage that emerges early during prostate development and provide new insights into the lineage relationships of the prostate epithelium.
    Keywords:  developmental biology; mouse; regenerative medicine; stem cells
    DOI:  https://doi.org/10.7554/eLife.60225
  39. Cell Metab. 2020 Oct 06. pii: S1550-4131(20)30490-3. [Epub ahead of print]32(4): 561-574.e7
    Exposure to Static Magnetic and Electric Fields Treats Type 2 Diabetes.
    Calvin S Carter, Sunny C Huang, Charles C Searby, Benjamin Cassaidy, Michael J Miller, Wojciech J Grzesik, Ted B Piorczynski, Thomas K Pak, Susan A Walsh, Michael Acevedo, Qihong Zhang, Kranti A Mapuskar, Ginger L Milne, Antentor O Hinton, Deng-Fu Guo, Robert Weiss, Kyle Bradberry, Eric B Taylor, Adam J Rauckhorst, David W Dick, Vamsidhar Akurathi, Kelly C Falls-Hubert, Brett A Wagner, Walter A Carter, Kai Wang, Andrew W Norris, Kamal Rahmouni, Garry R Buettner, Jason M Hansen, Douglas R Spitz, E Dale Abel, Val C Sheffield.
      Aberrant redox signaling underlies the pathophysiology of many chronic metabolic diseases, including type 2 diabetes (T2D). Methodologies aimed at rebalancing systemic redox homeostasis have had limited success. A noninvasive, sustained approach would enable the long-term control of redox signaling for the treatment of T2D. We report that static magnetic and electric fields (sBE) noninvasively modulate the systemic GSH-to-GSSG redox couple to promote a healthier systemic redox environment that is reducing. Strikingly, when applied to mouse models of T2D, sBE rapidly ameliorates insulin resistance and glucose intolerance in as few as 3 days with no observed adverse effects. Scavenging paramagnetic byproducts of oxygen metabolism with SOD2 in hepatic mitochondria fully abolishes these insulin sensitizing effects, demonstrating that mitochondrial superoxide mediates induction of these therapeutic changes. Our findings introduce a remarkable redox-modulating phenomenon that exploits endogenous electromagneto-receptive mechanisms for the noninvasive treatment of T2D, and potentially other redox-related diseases.
    Keywords:  ROS; electromagnetic fields; glutathione; insulin resistance; liver; mitochondria; radical pair mechanism; redox; superoxide; type 2 diabetes
    DOI:  https://doi.org/10.1016/j.cmet.2020.09.012
  40. Cell Metab. 2020 Oct 06. pii: S1550-4131(20)30478-2. [Epub ahead of print]32(4): 689
    A2A Receptor Activation Attenuates Hypertensive Cardiac Remodeling via Promoting Brown Adipose Tissue-Derived FGF21.
    Cheng-Chao Ruan, Ling-Ran Kong, Xiao-Hui Chen, Yu Ma, Xiao-Xi Pan, Ze-Bei Zhang, Ping-Jin Gao.
      
    DOI:  https://doi.org/10.1016/j.cmet.2020.08.018
  41. Nature. 2020 Oct 07.
    eIF2α controls memory consolidation via excitatory and somatostatin neurons.
    Vijendra Sharma, Rapita Sood, Abdessattar Khlaifia, Mohammad Javad Eslamizade, Tzu-Yu Hung, Danning Lou, Azam Asgarihafshejani, Maya Lalzar, Stephen J Kiniry, Matthew P Stokes, Noah Cohen, Alissa J Nelson, Kathryn Abell, Anthony P Possemato, Shunit Gal-Ben-Ari, Vinh T Truong, Peng Wang, Adonis Yiannakas, Fatemeh Saffarzadeh, A Claudio Cuello, Karim Nader, Randal J Kaufman, Mauro Costa-Mattioli, Pavel V Baranov, Albert Quintana, Elisenda Sanz, Arkady Khoutorsky, Jean-Claude Lacaille, Kobi Rosenblum, Nahum Sonenberg.
      An important tenet of learning and memory is the notion of a molecular switch that promotes the formation of long-term memory1-4. The regulation of proteostasis is a critical and rate-limiting step in the consolidation of new memories5-10. One of the most effective and prevalent ways to enhance memory is by regulating the synthesis of proteins controlled by the translation initiation factor eIF211. Phosphorylation of the α-subunit of eIF2 (p-eIF2α), the central component of the integrated stress response (ISR), impairs long-term memory formation in rodents and birds11-13. By contrast, inhibiting the ISR by mutating the eIF2α phosphorylation site, genetically11 and pharmacologically inhibiting the ISR kinases14-17, or mimicking reduced p-eIF2α with the ISR inhibitor ISRIB11, enhances long-term memory in health and disease18. Here we used molecular genetics to dissect the neuronal circuits by which the ISR gates cognitive processing. We found that learning reduces eIF2α phosphorylation in hippocampal excitatory neurons and a subset of hippocampal inhibitory neurons (those that express somatostatin, but not parvalbumin). Moreover, ablation of p-eIF2α in either excitatory or somatostatin-expressing (but not parvalbumin-expressing) inhibitory neurons increased general mRNA translation, bolstered synaptic plasticity and enhanced long-term memory. Thus, eIF2α-dependent mRNA translation controls memory consolidation via autonomous mechanisms in excitatory and somatostatin-expressing inhibitory neurons.
    DOI:  https://doi.org/10.1038/s41586-020-2805-8
  42. Autophagy. 2020 Oct 04.
    The Structure of Human ATG9A and Its Interplay with the Lipid Bilayer.
    Anirban Banerjee, Carlos M Guardia, Eric T Christenson, Wenchang Zhou, Xiao-Feng Tan, Tengfei Lian, José D Faraldo-Gómez, Juan S Bonifacino, Jiansen Jiang.
      ATG9, the only transmembrane protein in the core macroautophagy/autophagy machinery, is a key player in the early stages of autophagosome formation. Yet, the lack of a high-resolution structure of ATG9 was a major impediment in understanding its three-dimensional organization and function. We recently solved a high-resolution cryoEM structure of the ubiquitously expressed human ATG9A isoform. The structure revealed that ATG9A is a domain-swapped homotrimer with a unique fold, and has an internal network of branched cavities. In cellulo analyses demonstrated the functional importance of the cavity-lining residues. These cavities could serve as conduits for transport of hydrophilic moieties, such as lipid headgroups, across the bilayer. Finally, structure-guided molecular dynamics predicted that ATG9A has membrane-bending properties, which is consistent with its localization to highly curved membranes.
    Keywords:  ATG9A; autophagosome; cryo-EM; membrane curvature; molecular dynamics; transmembrane protein
    DOI:  https://doi.org/10.1080/15548627.2020.1830522
  43. J Cell Sci. 2020 Oct 08. pii: jcs234930. [Epub ahead of print]133(19):
    Ras, PI3K and mTORC2 - three's a crowd?
    Stephen F Smith, Shannon E Collins, Pascale G Charest.
      The Ras oncogene is notoriously difficult to target with specific therapeutics. Consequently, there is interest to better understand the Ras signaling pathways to identify potential targetable effectors. Recently, the mechanistic target of rapamycin complex 2 (mTORC2) was identified as an evolutionarily conserved Ras effector. mTORC2 regulates essential cellular processes, including metabolism, survival, growth, proliferation and migration. Moreover, increasing evidence implicate mTORC2 in oncogenesis. Little is known about the regulation of mTORC2 activity, but proposed mechanisms include a role for phosphatidylinositol (3,4,5)-trisphosphate - which is produced by class I phosphatidylinositol 3-kinases (PI3Ks), well-characterized Ras effectors. Therefore, the relationship between Ras, PI3K and mTORC2, in both normal physiology and cancer is unclear; moreover, seemingly conflicting observations have been reported. Here, we review the evidence on potential links between Ras, PI3K and mTORC2. Interestingly, data suggest that Ras and PI3K are both direct regulators of mTORC2 but that they act on distinct pools of mTORC2: Ras activates mTORC2 at the plasma membrane, whereas PI3K activates mTORC2 at intracellular compartments. Consequently, we propose a model to explain how Ras and PI3K can differentially regulate mTORC2, and highlight the diversity in the mechanisms of mTORC2 regulation, which appear to be determined by the stimulus, cell type, and the molecularly and spatially distinct mTORC2 pools.
    Keywords:  Mechanistic target of rapamycin complex 2; Phosphatidylinositol 3-kinase; Ras GTPase
    DOI:  https://doi.org/10.1242/jcs.234930
  44. Nat Rev Cancer. 2020 Oct 06.
    Metabolic benefits of mitochondrial DNA mutations.
    Sarah Seton-Rogers.
      
    DOI:  https://doi.org/10.1038/s41568-020-00309-x
  45. Nat Rev Cancer. 2020 Oct 06.
    Cancer progression and the invisible phase of metastatic colonization.
    Christoph A Klein.
      Metastatic dissemination occurs very early in the malignant progression of a cancer but the clinical manifestation of metastases often takes years. In recent decades, 5-year survival of patients with many solid cancers has increased due to earlier detection, local disease control and adjuvant therapies. As a consequence, we are confronted with an increase in late relapses as more antiproliferative cancer therapies prolong disease courses, raising questions about how cancer cells survive, evolve or stop growing and finally expand during periods of clinical latency. I argue here that the understanding of early metastasis formation, particularly of the currently invisible phase of metastatic colonization, will be essential for the next stage in adjuvant therapy development that reliably prevents metachronous metastasis.
    DOI:  https://doi.org/10.1038/s41568-020-00300-6
  46. Proc Natl Acad Sci U S A. 2020 Oct 05. pii: 202008303. [Epub ahead of print]
    How the T cell signaling network processes information to discriminate between self and agonist ligands.
    Raman S Ganti, Wan-Lin Lo, Darren B McAffee, Jay T Groves, Arthur Weiss, Arup K Chakraborty.
      T cells exhibit remarkable sensitivity and selectivity in detecting and responding to agonist peptides (p) bound to MHC molecules in a sea of self pMHC molecules. Despite much work, understanding of the underlying mechanisms of distinguishing such ligands remains incomplete. Here, we quantify T cell discriminatory capacity using channel capacity, a direct measure of the signaling network's ability to discriminate between antigen-presenting cells (APCs) displaying either self ligands or a mixture of self and agonist ligands. This metric shows how differences in information content between these two types of peptidomes are decoded by the topology and rates of kinetic proofreading signaling steps inside T cells. Using channel capacity, we constructed numerically substantiated hypotheses to explain the discriminatory role of a recently identified slow LAT Y132 phosphorylation step. Our results revealed that in addition to the number and kinetics of sequential signaling steps, a key determinant of discriminatory capability is spatial localization of a minimum number of these steps to the engaged TCR. Biochemical and imaging experiments support these findings. Our results also reveal the discriminatory role of early negative feedback and necessary amplification conferred by late positive feedback.
    Keywords:  T cell receptor ligand discrimination; kinetic proofreading; modeling; self/agonist peptides
    DOI:  https://doi.org/10.1073/pnas.2008303117
  47. Proc Natl Acad Sci U S A. 2020 Oct 05. pii: 201922618. [Epub ahead of print]
    Chronicling changes in the somatosensory neurons after peripheral nerve injury.
    Shrinivasan Raghuraman, Jennifer Y Xie, Mario J Giacobassi, Jortan O Tun, Kevin Chase, Dong Lu, Russell W Teichert, Frank Porreca, Baldomero M Olivera.
      Current drug discovery efforts focus on identifying lead compounds acting on a molecular target associated with an established pathological state. Concerted molecular changes that occur in specific cell types during disease progression have generally not been identified. Here, we used constellation pharmacology to investigate rat dorsal root ganglion neurons using two models of peripheral nerve injury: chronic constriction injury (CCI) and spinal nerve ligation (SNL). In these well-established models of neuropathic pain, we show that the onset of chronic pain is accompanied by a dramatic, previously unreported increase in the number of bradykinin-responsive neurons, with larger increases observed after SNL relative to CCI. To define the neurons with altered expression, we charted the temporal course of molecular changes following 1, 3, 6, and 14 d after SNL injury and demonstrated that specific molecular changes have different time courses during the progression to a pain state. In particular, ATP receptors up-regulated on day 1 postinjury, whereas the increase in bradykinin receptors was gradual after day 3 postinjury. We specifically tracked changes in two subsets of neurons: peptidergic and nonpeptidergic nociceptors. Significant increases occurred in ATP responses in nAChR-expressing isolectin B4+ nonpeptidergic neurons 1 d postinjury, whereas peptidergic neurons did not display any significant change. We propose that remodeling of ion channels and receptors occurs in a concerted and cell-specific manner, resulting in the appearance of bradykinin-responsive neuronal subclasses that are relevant to chronic pain.
    Keywords:  bradykinin; cell types; constellation pharmacology; dorsal root ganglion; nerve injury
    DOI:  https://doi.org/10.1073/pnas.1922618117
  48. Nat Rev Cancer. 2020 Oct 08.
    Non-genetic mechanisms of therapeutic resistance in cancer.
    Jean-Christophe Marine, Sarah-Jane Dawson, Mark A Dawson.
      Therapeutic resistance continues to be an indominable foe in our ambition for curative cancer treatment. Recent insights into the molecular determinants of acquired treatment resistance in the clinical and experimental setting have challenged the widely held view of sequential genetic evolution as the primary cause of resistance and brought into sharp focus a range of non-genetic adaptive mechanisms. Notably, the genetic landscape of the tumour and the non-genetic mechanisms used to escape therapy are frequently linked. Remarkably, whereas some oncogenic mutations allow the cancer cells to rapidly adapt their transcriptional and/or metabolic programme to meet and survive the therapeutic pressure, other oncogenic drivers convey an inherent cellular plasticity to the cancer cell enabling lineage switching and/or the evasion of anticancer immunosurveillance. The prevalence and diverse array of non-genetic resistance mechanisms pose a new challenge to the field that requires innovative strategies to monitor and counteract these adaptive processes. In this Perspective we discuss the key principles of non-genetic therapy resistance in cancer. We provide a perspective on the emerging data from clinical studies and sophisticated cancer models that have studied various non-genetic resistance pathways and highlight promising therapeutic avenues that may be used to negate and/or counteract the non-genetic adaptive pathways.
    DOI:  https://doi.org/10.1038/s41568-020-00302-4
  49. Nat Commun. 2020 10 07. 11(1): 5037
    Tracing the cellular basis of islet specification in mouse pancreas.
    Magdalena K Sznurkowska, Edouard Hannezo, Roberta Azzarelli, Lemonia Chatzeli, Tatsuro Ikeda, Shosei Yoshida, Anna Philpott, Benjamin D Simons.
      Pancreatic islets play an essential role in regulating blood glucose level. Although the molecular pathways underlying islet cell differentiation are beginning to be resolved, the cellular basis of islet morphogenesis and fate allocation remain unclear. By combining unbiased and targeted lineage tracing, we address the events leading to islet formation in the mouse. From the statistical analysis of clones induced at multiple embryonic timepoints, here we show that, during the secondary transition, islet formation involves the aggregation of multiple equipotent endocrine progenitors that transition from a phase of stochastic amplification by cell division into a phase of sublineage restriction and limited islet fission. Together, these results explain quantitatively the heterogeneous size distribution and degree of polyclonality of maturing islets, as well as dispersion of progenitors within and between islets. Further, our results show that, during the secondary transition, α- and β-cells are generated in a contemporary manner. Together, these findings provide insight into the cellular basis of islet development.
    DOI:  https://doi.org/10.1038/s41467-020-18837-3
  50. Nat Commun. 2020 10 06. 11(1): 5011
    Predicting cell-to-cell communication networks using NATMI.
    Rui Hou, Elena Denisenko, Huan Ting Ong, Jordan A Ramilowski, Alistair R R Forrest.
      Development of high throughput single-cell sequencing technologies has made it cost-effective to profile thousands of cells from diverse samples containing multiple cell types. To study how these different cell types work together, here we develop NATMI (Network Analysis Toolkit for Multicellular Interactions). NATMI uses connectomeDB2020 (a database of 2293 manually curated ligand-receptor pairs with literature support) to predict and visualise cell-to-cell communication networks from single-cell (or bulk) expression data. Using multiple published single-cell datasets we demonstrate how NATMI can be used to identify (i) the cell-type pairs that are communicating the most (or most specifically) within a network, (ii) the most active (or specific) ligand-receptor pairs active within a network, (iii) putative highly-communicating cellular communities and (iv) differences in intercellular communication when profiling given cell types under different conditions. Furthermore, analysis of the Tabula Muris (organism-wide) atlas confirms our previous prediction that autocrine signalling is a major feature of cell-to-cell communication networks, while also revealing that hundreds of ligands and their cognate receptors are co-expressed in individual cells suggesting a substantial potential for self-signalling.
    DOI:  https://doi.org/10.1038/s41467-020-18873-z
  51. Trends Biochem Sci. 2020 Oct 01. pii: S0968-0004(20)30229-2. [Epub ahead of print]
    How Lysosomes Sense, Integrate, and Cope with Stress.
    Paul Saftig, Rosa Puertollano.
      Lysosomes are in the center of the cellular control of catabolic and anabolic processes. These membrane-surrounded acidic organelles contain around 70 hydrolases, 200 membrane proteins, and numerous accessory proteins associated with the cytosolic surface of lysosomes. Accessory and transmembrane proteins assemble in signaling complexes that sense and integrate multiple signals and transmit the information to the nucleus. This communication allows cells to respond to changes in multiple environmental conditions, including nutrient levels, pathogens, energy availability, and lysosomal damage, with the goal of restoring cellular homeostasis. This review summarizes our current understanding of the major molecular players and known pathways that are involved in control of metabolic and stress responses that either originate from lysosomes or regulate lysosomal functions.
    Keywords:  TFEB; autophagy; lysosomes; mTOR; nutrient sensing; transcription factors
    DOI:  https://doi.org/10.1016/j.tibs.2020.09.004
  52. FEBS J. 2020 Oct 08.
    The multifaceted role of cell cycle regulators in the coordination of growth and metabolism.
    Katharina Huber, Albert Mestres-Arenes, Lluis Fajas, Lucia C Leal-Esteban.
      Adapting to changes in nutrient availability and environmental conditions is a fundamental property of cells. This adaptation requires a multi-directional coordination between metabolism, growth and the cell cycle regulators (consisting of the family of cyclin-dependent kinases (CDKs), their regulatory subunits known as cyclins, CDK inhibitors, the retinoblastoma family members and the E2F transcription factors). Deciphering the mechanisms accountable for this coordination is crucial for understanding various patho-physiological processes. While it is well established that metabolism and growth affect cell division, this review will focus on recent observations that demonstrate how cell cycle regulators coordinate metabolism, cell cycle progression and growth. We will discuss how the cell cycle regulators directly regulate metabolic enzymes and pathways and summarize their involvement in the endolysosomal pathway and in the functions and dynamics of mitochondria.
    Keywords:  Cell cycle regulators; cell growth; endolysosomes; metabolism; mitochondria
    DOI:  https://doi.org/10.1111/febs.15586
  53. J Exp Clin Cancer Res. 2020 Oct 07. 39(1): 209
    Calreticulin promotes EMT in pancreatic cancer via mediating Ca2+ dependent acute and chronic endoplasmic reticulum stress.
    Weiwei Sheng, Guosen Wang, Jingtong Tang, Xiaoyang Shi, Rongxian Cao, Jian Sun, Yi Heng Lin, Chao Jia, Chuanping Chen, Jianping Zhou, Ming Dong.
       BACKGROUND: Our previous study showed that calreticulin (CRT) promoted EGF-induced epithelial-mesenchymal transition (EMT) in pancreatic cancer (PC) via Integrin/EGFR-ERK/MAPK signaling. We next investigated the novel signal pathway and molecular mechanism involving the oncogenic role of CRT in PC.
    METHODS: We investigated the potential role and mechanism of CRT in regulating intracellular free Ca2+ dependent acute and chronic endoplasmic reticulum stress (ERS)-induced EMT in PC in vitro and vivo.
    RESULTS: Thapsigargin (TG) induced acute ERS via increasing intracellular free Ca2+ in PC cells, which was reversed by CRT silencing. Additionally, CRT silencing inhibited TG-induced EMT in vitro by reversing TG-induced changes of the key proteins in EMT signaling (ZO-1, E-cadherin and Slug) and ERK/MAPK signaling (pERK). TG-promoted cell invasion and migration was also rescued by CRT silencing but enhanced by IRE1α silencing (one of the key stressors in unfolded protein response). Meanwhile, CRT was co-immunoprecipitated and co-localized with IRE1α in vitro and its silencing led to the chronic ERS via upregulating IRE1α independent of IRE1-XBP1 axis. Moreover, CRT silencing inhibited IRE1α silencing-promoted EMT, including inhibiting the activation of EMT and ERK/MAPK signaling and the promotion of cell mobility. In vivo, CRT silencing decreased subcutaneous tumor size and distant liver metastasis following with the increase of IRE1α expression. A negative relationship between CRT and IRE1α was also observed in clinical PC samples, which coordinately promoted the advanced clinical stages and poor prognosis of PC patients.
    CONCLUSIONS: CRT promotes EMT in PC via mediating intracellular free Ca2+ dependent TG-induced acute ERS and IRE1α-mediated chronic ERS via Slug and ERK/MAPK signaling.
    Keywords:  Calreticulin; Endoplasmic reticulum stress; Epithelial mesenchymal transition; IRE1α; Intracellular free Ca2 +; Pancreatic cancer
    DOI:  https://doi.org/10.1186/s13046-020-01702-y
  54. Curr Biol. 2020 Oct 05. pii: S0960-9822(20)31257-4. [Epub ahead of print]30(19): R1090-R1092
    Membrane Biology: Disentangling Cellular Lipid Connections.
    Britta Brügger.
      Biological membranes consist of a surprisingly high number of different lipid species. Little is known about how individual lipids cooperate in modulating cellular functions. A new study suggests an intricate interplay of sphingolipids with ether lipids in vesicular transport.
    DOI:  https://doi.org/10.1016/j.cub.2020.08.067
  55. Br J Cancer. 2020 Oct 07.
    Suppression of pancreatic cancer liver metastasis by secretion-deficient ITIH5.
    Eric D Young, Sharon J Manley, Thomas C Beadnell, Alexander E Shearin, Ken Sasaki, Rosalyn Zimmerman, Evan Kauffman, Carolyn J Vivian, Aishwarya Parasuram, Tomoo Iwakuma, Paul M Grandgenett, Michael A Hollingsworth, Maura O'Neil, Danny R Welch.
       BACKGROUND: Previously, we identified ITIH5 as a suppressor of pancreatic ductal adenocarcinoma (PDAC) metastasis in experimental models. Expression of ITIH5 correlated with decreased cell motility, invasion and metastasis without significant inhibition of primary tumour growth. Here, we tested whether secretion of ITIH5 is required to suppress liver metastasis and sought to understand the role of ITIH5 in human PDAC.
    METHODS: We expressed mutant ITIH5 with deletion of the N-terminal secretion sequence (ITIH5Δs) in highly metastatic human PDAC cell lines. We used a human tissue microarray (TMA) to compare ITIH5 levels in uninvolved pancreas, primary and metastatic PDAC.
    RESULTS: Secretion-deficient ITIH5Δs was sufficient to suppress liver metastasis. Similar to secreted ITIH5, expression of ITIH5Δs was associated with rounded cell morphology, reduced cell motility and reduction of liver metastasis. Expression of ITIH5 is low in both human primary PDAC and matched metastases.
    CONCLUSIONS: Metastasis suppression by ITIH5 may be mediated by an intracellular mechanism. In human PDAC, loss of ITIH5 may be an early event and ITIH5-low PDAC cells in primary tumours may be selected for liver metastasis. Further defining the ITIH5-mediated pathway in PDAC could establish future therapeutic exploitation of this biology and reduce morbidity and mortality associated with PDAC metastasis.
    DOI:  https://doi.org/10.1038/s41416-020-01093-z
  56. Autophagy. 2020 Oct 05. 1-18
    Secretory autophagy machinery and vesicular trafficking are involved in HMGB1 secretion.
    Young Hun Kim, Man Sup Kwak, Bin Lee, Jae Min Shin, Sowon Aum, In Ho Park, Min Goo Lee, Jeon-Soo Shin.
      Nuclear protein HMGB1 is secreted in response to various stimuli and functions as a danger-associated molecular pattern. Extracellular HMGB1 induces inflammation, cytokine production, and immune cell recruitment via activation of various receptors. As HMGB1 does not contain an endoplasmic reticulum-targeting signal peptide, HMGB1 is secreted via the endoplasmic reticulum-Golgi independently via an unconventional secretion pathway. However, the mechanism underlying HMGB1 secretion remains largely unknown. Here, we investigated the role of secretory autophagy machinery and vesicular trafficking in HMGB1 secretion. We observed that HSP90AA1 (heat shock protein 90 alpha family class A member 1), a stress-inducible protein, regulates the translocation of HMGB1 from the nucleus to the cytoplasm and its secretion through direct interaction. Additionally, geldanamycin, an HSP90AA1 inhibitor, reduced HMGB1 secretion. GORASP2/GRASP55 (golgi reassembly stacking protein 2), ARF1Q71L (ADP ribosylation factor 1), and SAR1AT39N (secretion associated Ras related GTPase 1A), which promoted unconventional protein secretion, increased HMGB1 secretion. HMGB1 secretion was inhibited by an early autophagy inhibitor and diminished in ATG5-deficient cells even when GORASP2 was overexpressed. In contrast, a late autophagy inhibitor increased HMGB1 secretion under the same conditions. The multivesicular body formation inhibitor GW4869 dramatically decreased HMGB1 secretion under HMGB1 secretion-inducing conditions. Thus, we demonstrated that secretory autophagy and multivesicular body formation mediate HMGB1 secretion.
    Keywords:  GORASP2; HMGB1; HSP90AA1; MVB formation; autophagy; unconventional protein secretion
    DOI:  https://doi.org/10.1080/15548627.2020.1826690
  57. Biol Chem. 2020 Oct 09. pii: /j/bchm.ahead-of-print/hsz-2020-0231/hsz-2020-0231.xml. [Epub ahead of print]
    Kill one or kill the many: interplay between mitophagy and apoptosis.
    Simone Wanderoy, J Tabitha Hees, Ramona Klesse, Frank Edlich, Angelika B Harbauer.
      Mitochondria are key players of cellular metabolism, Ca2+ homeostasis, and apoptosis. The functionality of mitochondria is tightly regulated, and dysfunctional mitochondria are removed via mitophagy, a specialized form of autophagy that is compromised in hereditary forms of Parkinson's disease. Through mitophagy, cells are able to cope with mitochondrial stress until the damage becomes too great, which leads to the activation of pro-apoptotic BCL-2 family proteins located on the outer mitochondrial membrane. Active pro-apoptotic BCL-2 proteins facilitate the release of cytochrome c from the mitochondrial intermembrane space (IMS) into the cytosol, committing the cell to apoptosis by activating a cascade of cysteinyl-aspartate specific proteases (caspases). We are only beginning to understand how the choice between mitophagy and the activation of caspases is determined on the mitochondrial surface. Intriguingly in neurons, caspase activation also plays a non-apoptotic role in synaptic plasticity. Here we review the current knowledge on the interplay between mitophagy and caspase activation with a special focus on the central nervous system.
    Keywords:  BCL-2 family; PINK1; Parkin; Parkinson’s disease; caspase-3; synaptic plasticity
    DOI:  https://doi.org/10.1515/hsz-2020-0231
  58. Cell Stress. 2020 Aug 18. 4(10): 230-247
    Endocytosis in the adaptation to cellular stress.
    Tania López-Hernández, Volker Haucke, Tanja Maritzen.
      Cellular life is challenged by a multitude of stress conditions, triggered for example by alterations in osmolarity, oxygen or nutrient supply. Hence, cells have developed sophisticated stress responses to cope with these challenges. Some of these stress programs such as the heat shock response are understood in great detail, while other aspects remain largely elusive including potential stress-dependent adaptations of the plasma membrane proteome. The plasma membrane is not only the first point of encounter for many types of environmental stress, but given the diversity of receptor proteins and their associated molecules also represents the site at which many cellular signal cascades originate. Since these signaling pathways affect virtually all aspects of cellular life, changes in the plasma membrane proteome appear ideally suited to contribute to the cellular adaptation to stress. The most rapid means to alter the cell surface proteome in response to stress is by alterations in endocytosis. Changes in the overall endocytic flux or in the endocytic regulation of select proteins conceivably can help to counteract adverse environmental conditions. In this review we summarize recent data regarding stress-induced changes in endocytosis and discuss how these changes might contribute to the cellular adaptation to stress in different systems. Future studies will be needed to uncover the underlying mechanisms in detail and to arrive at a coherent picture.
    Keywords:  cancer; clathrin-mediated endocytosis; hypoxia; mechanical stress; nutrient signaling; osmotic stress; oxidative stress
    DOI:  https://doi.org/10.15698/cst2020.10.232
  59. Cancer Discov. 2020 Oct 07. pii: CD-20-0318. [Epub ahead of print]
    The hepatic microenvironment uniquely protects leukemia cells through induction of growth and survival pathways mediated by LIPG.
    Haobin Ye, Mohammad Minhajuddin, Anna Krug, Shanshan Pei, Chih-Hsing Chou, Rachel Culp-Hill, Jessica Ponder, Erik De Bloois, Björn Schniedewind, Maria L Amaya, Anagha Inguva, Brett M Stevens, Daniel A Pollyea, Uwe Christians, H Leighton Grimes, Angelo D'Alessandro, Craig T Jordan.
      Due to the disseminated nature of leukemia, malignant cells are exposed to many different tissue microenvironments, including a variety of extramedullary sites. In the present study, we demonstrate that leukemic cells residing in the liver display unique biological properties, and also contribute to systemic changes that influence physiological responses to chemotherapy. Specifically, the liver microenvironment induces metabolic adaptations via up-regulating expression of endothelial lipase (LIPG) in leukemia cells, which not only stimulates tumor cell proliferation through polyunsaturated fatty acid (PUFA) mediated pathways, but also promotes survival by stabilizing anti-apoptotic proteins. Additionally, hepatic infiltration and tissue damage caused by malignant cells induces release of liver-derived enzymes capable of degrading chemotherapy drugs, an event which further protects leukemia cells from conventional therapies. Together, these studies demonstrate a unique role for liver in modulating the pathogenesis of leukemic disease and suggest that the hepatic microenvironment may protect leukemia cells from chemotherapeutic challenge.
    DOI:  https://doi.org/10.1158/2159-8290.CD-20-0318
  60. Proc Natl Acad Sci U S A. 2020 Oct 05. pii: 202008801. [Epub ahead of print]
    Extracellular matrix plasticity as a driver of cell spreading.
    Joshua M Grolman, Philipp Weinand, David J Mooney.
      Mammalian cell morphology has been linked to the viscoelastic properties of the adhesion substrate, which is particularly relevant in biological processes such as wound repair and embryonic development where cell spreading and migration are critical. Plastic deformation, degradation, and relaxation of stress are typically coupled in biomaterial systems used to explore these effects, making it unclear which variable drives cell behavior. Here we present a nondegradable polymer architecture that specifically decouples irreversible creep from stress relaxation and modulus. We demonstrate that network plasticity independently controls mesenchymal stem cell spreading through a biphasic relationship dependent on cell-intrinsic forces, and this relationship can be shifted by inhibiting actomyosin contractility. Kinetic Monte Carlo simulations also show strong correlation with experimental cell spreading data as a function of the extracellular matrix (ECM) plasticity. Furthermore, plasticity regulates many ECM adhesion and remodeling genes. Altogether, these findings confirm a key role for matrix plasticity in stem cell biophysics, and we anticipate this will have ramifications in the design of biomaterials to enhance therapeutic applications of stem cells.
    Keywords:  biomaterials; extracellular matrix; plasticity; stem cell; viscoelasticity
    DOI:  https://doi.org/10.1073/pnas.2008801117
  61. EMBO Rep. 2020 Oct 05. e51015
    Respiratory supercomplexes enhance electron transport by decreasing cytochrome c diffusion distance.
    Jens Berndtsson, Andreas Aufschnaiter, Sorbhi Rathore, Lorena Marin-Buera, Hannah Dawitz, Jutta Diessl, Verena Kohler, Antoni Barrientos, Sabrina Büttner, Flavia Fontanesi, Martin Ott.
      Respiratory chains are crucial for cellular energy conversion and consist of multi-subunit complexes that can assemble into supercomplexes. These structures have been intensively characterized in various organisms, but their physiological roles remain unclear. Here, we elucidate their function by leveraging a high-resolution structural model of yeast respiratory supercomplexes that allowed us to inhibit supercomplex formation by mutation of key residues in the interaction interface. Analyses of a mutant defective in supercomplex formation, which still contains fully functional individual complexes, show that the lack of supercomplex assembly delays the diffusion of cytochrome c between the separated complexes, thus reducing electron transfer efficiency. Consequently, competitive cellular fitness is severely reduced in the absence of supercomplex formation and can be restored by overexpression of cytochrome c. In sum, our results establish how respiratory supercomplexes increase the efficiency of cellular energy conversion, thereby providing an evolutionary advantage for aerobic organisms.
    Keywords:  bioenergetics; competitive fitness; cryo-EM; mitochondria; respiratory chain supercomplexes
    DOI:  https://doi.org/10.15252/embr.202051015
  62. Cell Host Microbe. 2020 Sep 30. pii: S1931-3128(20)30505-9. [Epub ahead of print]
    Lysosome Fusion Maintains Phagosome Integrity during Fungal Infection.
    Johannes Westman, Glenn F W Walpole, Lydia Kasper, Bessie Y Xue, Osama Elshafee, Bernhard Hube, Sergio Grinstein.
      Phagosomes must maintain membrane integrity to exert their microbicidal function. Some microorganisms, however, survive and grow within phagosomes. In such instances, phagosomes must expand to avoid rupture and microbial escape. We studied whether phagosomes regulate their size to preserve integrity during infection with the fungal pathogen Candida albicans. Phagosomes release calcium as C. albicans hyphae elongate, inducing lysosome recruitment and insertion, thereby increasing the phagosomal surface area. As hyphae grow, the expanding phagosome consumes the majority of free lysosomes. Simultaneously, lysosome biosynthesis is stimulated by activation of TFEB, a transcriptional regulator of lysosomal biogenesis. Preventing lysosomal insertion causes phagosomal rupture, NLRP3 inflammasome activation, IL-1β secretion and host-cell death. Whole-genome transcriptomic analysis demonstrate that stress responses elicited in C. albicans upon engulfment are reversed if phagosome expansion is prevented. Our findings reveal a mechanism whereby phagosomes maintain integrity while expanding, ensuring that growing pathogens remain entrapped within this microbicidal compartment.
    Keywords:  Candida albicans; NLRP3; calcium; fungi; hypha; inflammasome; lysosome; macrophage; phagocytosis; phagosome
    DOI:  https://doi.org/10.1016/j.chom.2020.09.004
  63. Elife. 2020 10 05. pii: e56749. [Epub ahead of print]9
    A powerful drug combination strategy targeting glutamine addiction for the treatment of human liver cancer.
    Haojie Jin, Siying Wang, Esther A Zaal, Cun Wang, Haiqiu Wu, Astrid Bosma, Fleur Jochems, Nikita Isima, Guangzhi Jin, Cor Lieftink, Roderick Beijersbergen, Celia R Berkers, Wenxin Qin, Rene Bernards.
      The dependency of cancer cells on glutamine may be exploited therapeutically as a new strategy for treating cancers that lack druggable driver genes. Here we found that human liver cancer was dependent on extracellular glutamine. However, targeting glutamine addiction using the glutaminase inhibitor CB-839 as monotherapy had a very limited anticancer effect, even against the most glutamine addicted human liver cancer cells. Using a chemical library, we identified V-9302, a novel inhibitor of glutamine transporter ASCT2, as sensitizing glutamine dependent (GD) cells to CB-839 treatment. Mechanically, a combination of CB-839 and V-9302 depleted glutathione and induced reactive oxygen species (ROS), resulting in apoptosis of GD cells. Moreover, this combination also showed tumor inhibition in HCC xenograft mouse models in vivo. Our findings indicate that dual inhibition of glutamine metabolism by targeting both glutaminase and glutamine transporter ASCT2 represents a potential novel treatment strategy for glutamine addicted liver cancers.
    Keywords:  CB-839; cancer biology; glutamine addiction; glutaminolysis; hepatocellular carcinoma; human
    DOI:  https://doi.org/10.7554/eLife.56749
  64. Nature. 2020 Oct;586(7828): 205-206
    Early onset of planet formation observed in a nascent star system.
    Patrick Sheehan.
      
    Keywords:  Astronomy and astrophysics; Exoplanets; Planetary science
    DOI:  https://doi.org/10.1038/d41586-020-02748-w
  65. Front Immunol. 2020 ;11 558169
    Topographical Distribution and Spatial Interactions of Innate and Semi-Innate Immune Cells in Pancreatic and Other Periampullary Adenocarcinoma.
    Sebastian Lundgren, Patrick Micke, Jacob Elebro, Margareta Heby, Ina Hrynchyk, Björn Nodin, Karin Leandersson, Artur Mezheyeuski, Karin Jirström.
       Background: The clinical management of pancreatic and other periampullary neoplasms remains challenging. In contrast to other cancer types, immunotherapies are largely ineffective, and the reason for the deprived immune response and the immune inhibiting cellular composition is only fragmentarily understood. The aim of this study was to comprehensively map the abundance, topographic distribution and spatial interaction of innate and innate-like immune cells in the tumor microenvironment of periampullary adenocarcinoma.
    Methods: Multiplexed immunofluorescent imaging was performed on tissue microarrays with tumors from a consecutive cohort of 175 patients with resected periampullary adenocarcinoma. To obtain a detailed spatial analysis of immune cell infiltration, two multiplex immune panels including antibodies against CD3, NKp46, CD56, CD68, CD163 and CD1a, CD208, CD123, CD15, CD68 and pan-cytokeratin were applied.
    Results: The infiltration of natural killer (NK) and NK-like T (NKT) cells was lower in malignant compared to benign tissue. NKT cells were more abundant in intestinal type compared to pancreatobiliary type tumors, and were associated with more favorable clinicopathological features and a prolonged survival. The interaction of NKp46+ NKT cells with macrophages was also associated with a prolonged survival.
    Conclusions: This study provides a comprehensive map of the innate immune landscape in periampullary adenocarcinoma. NK cells, and even more so NKT cells, are revealed to be central players in the local immune response in a clinically relevant context.
    Keywords:  dendritic cells; innate immunity; natural killer T-cells; natural killer cells; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2020.558169
  66. Mech Ageing Dev. 2020 Oct 03. pii: S0047-6374(20)30175-5. [Epub ahead of print]192 111379
    Sestrin family - the stem controlling healthy ageing.
    Alexander Haidurov, Andrei V Budanov.
      Sestrins are a family of stress-responsive antioxidant proteins responsible for regulation of cell viability and metabolism. The best known Sestrin targets are mTORC1 and mTORC2 kinases that control different cellular processes including growth, viability, autophagy, and mitochondrial metabolism. Inactivation of the single Sestrin gene in invertebrates has an adverse impact on their healthspan and longevity, whereas each of the three Sestrin genes in mammals and other vertebrate organisms has a different impact on maintenance of a particular tissue, affecting its stress tolerance, function and regenerative capability. As a result, Sestrins attenuate ageing and suppress development of many age-related diseases including myocardial infarction, muscle atrophy, diabetes, and immune dysfunction, but exacerbate development of chronic obstructive pulmonary disease. Moreover, Sestrins play opposite roles in carcinogenesis in different tissues. Stem cells support tissue remodelling that influences ageing, and Sestrins might suppress ageing and age-related pathologies through control of stem cell biology. In this review, we will discuss the potential link between Sestrins, stem cells, and ageing.
    Keywords:  Cell death; GATOR1/2; Mitochondria; Sestrin; mTORC1/2
    DOI:  https://doi.org/10.1016/j.mad.2020.111379
  67. Clin Geriatr Med. 2020 Nov;pii: S0749-0690(20)30051-3. [Epub ahead of print]36(4): 671-683
    Physical Activity and Healthy Aging.
    Elizabeth Eckstrom, Suvi Neukam, Leah Kalin, Jessica Wright.
      Healthy aging is the ability to maintain independence, purpose, vitality, and quality of life into old age despite unexpected medical conditions, accidents, and unhelpful social determinants of health. Exercise, or physical activity, is an important component of healthy aging, preventing or mitigating falls, pain, sarcopenia, osteoporosis, and cognitive impairment. A well-balanced exercise program includes daily aerobic, strength, balance, and flexibility components. Most older adults do not meet the currently recommended minutes of regular physical activity weekly. Counseling by health care providers may help older adults improve exercise habits, but it is also important to take advantage of community-based exercise opportunities.
    Keywords:  Exercise; Healthy aging; Older adults; Physical activity
    DOI:  https://doi.org/10.1016/j.cger.2020.06.009
  68. Lancet Oncol. 2020 Oct 05. pii: S1470-2045(20)30593-3. [Epub ahead of print]
    A roadmap for the early detection and diagnosis of cancer.
    Early Detection and Diagnosis Roadmap Steering Group
      
    DOI:  https://doi.org/10.1016/S1470-2045(20)30593-3
  69. Cancers (Basel). 2020 Oct 06. pii: E2871. [Epub ahead of print]12(10):
    High G2M Pathway Score Pancreatic Cancer is Associated with Worse Survival, Particularly after Margin-Positive (R1 or R2) Resection.
    Masanori Oshi, Stephanie Newman, Yoshihisa Tokumaru, Li Yan, Ryusei Matsuyama, Itaru Endo, Matthew H G Katz, Kazuaki Takabe.
      Pancreatic cancer is highly mortal due to uncontrolled cell proliferation. The G2M checkpoint pathway is an essential part of the cell cycle. We hypothesized that a high G2M pathway score is associated with cell proliferation and worse survival in pancreatic cancer patients. Gene set variation analysis using the Hallmark G2M checkpoint gene set was used as a score to analyze a total of 390 human pancreatic cancer patients from 3 cohorts (TCGA, GSE62452, GSE57495). High G2M score tumors enriched other cell proliferation genes sets as well as MKI67 expression, pathological grade, and proliferation score. Independent of other prognostic factors, G2M score was predictive of disease-specific survival in pancreatic cancer. High G2M tumor was associated with high mutation rate of KRAS and TP53 and significantly enriched these pathway gene sets, as well as high infiltration of Th2 cells. High G2M score consistently associated with worse overall survival in 3 cohorts, particularly in R1/2 resection, but not in R0. High G2M tumor in R1/2 highly enriched metabolic and cellular components' gene sets compared to R0. To our knowledge, this is the first study to use gene set variation analysis as a score to examine the clinical relevancy of the G2M pathway in pancreatic cancer.
    Keywords:  biomarker; cell cycle; gene set; pancreatic cancer; pathway analysis; tumor gene expression
    DOI:  https://doi.org/10.3390/cancers12102871
  70. Br J Cancer. 2020 Oct 07.
    Artificial selection for host resistance to tumour growth and subsequent cancer cell adaptations: an evolutionary arms race.
    Arig Ibrahim-Hashim, Kimberly Luddy, Dominique Abrahams, Pedro Enriquez-Navas, Sultan Damgaci, Jiqiang Yao, Tingan Chen, Marilyn M Bui, Robert J Gillies, Cliona O'Farrelly, Christina L Richards, Joel S Brown, Robert A Gatenby.
       BACKGROUND: Cancer progression is governed by evolutionary dynamics in both the tumour population and its host. Since cancers die with the host, each new population of cancer cells must reinvent strategies to overcome the host's heritable defences. In contrast, host species evolve defence strategies over generations if tumour development limits procreation.
    METHODS: We investigate this "evolutionary arms race" through intentional breeding of immunodeficient SCID and immunocompetent Black/6 mice to evolve increased tumour suppression. Over 10 generations, we injected Lewis lung mouse carcinoma cells [LL/2-Luc-M38] and selectively bred the two individuals with the slowest tumour growth at day 11. Their male progeny were hosts in the subsequent round.
    RESULTS: The evolved SCID mice suppressed tumour growth through biomechanical restriction from increased mesenchymal proliferation, and the evolved Black/6 mice suppressed tumour growth by increasing immune-mediated killing of cancer cells. However, transcriptomic changes of multicellular tissue organisation and function genes allowed LL/2-Luc-M38 cells to adapt through increased matrix remodelling in SCID mice, and reduced angiogenesis, increased energy utilisation and accelerated proliferation in Black/6 mice.
    CONCLUSION: Host species can rapidly evolve both immunologic and non-immunologic tumour defences. However, cancer cell plasticity allows effective phenotypic and population-based counter strategies.
    DOI:  https://doi.org/10.1038/s41416-020-01110-1
  71. Nature. 2020 Oct 07.
    Pioneers of revolutionary CRISPR gene editing win chemistry Nobel.
    Heidi Ledford, Ewen Callaway.
      
    DOI:  https://doi.org/10.1038/d41586-020-02765-9
  72. Biophys J. 2020 Oct 06. pii: S0006-3495(20)30678-0. [Epub ahead of print]119(7): 1301-1308
    Ratchetaxis in Channels: Entry Point and Local Asymmetry Set Cell Directions in Confinement.
    Emilie Le Maout, Simon Lo Vecchio, Praveen Kumar Korla, Jim Jinn-Chyuan Sheu, Daniel Riveline.
      Cell motility is essential in a variety of biological phenomena ranging from early development to organ homeostasis and diseases. This phenomenon has mainly been studied and characterized on flat surfaces in vitro, whereas such conditions are rarely observed in vivo. Recently, cell motion in three-dimensional microfabricated channels was reported to be possible, and it was shown that confined cells push on walls. However, rules setting cell directions in this context have not yet been characterized. Here, we show by using assays that ratchetaxis operates in three-dimensional ratchets in fibroblasts and epithelial cancerous cells. Open ratchets rectify cell motion, whereas closed ratchets impose direct cell migration along channels set by the cell orientation at the channel entry point. We also show that nuclei are pressed in constriction zones through mechanisms involving dynamic asymmetries of focal contacts, stress fibers, and intermediate filaments. Interestingly, cells do not pass these constricting zones when they contain a defective keratin fusion protein implicated in squamous cancer. By combining ratchetaxis with chemical gradients, we finally report that cells are sensitive to local asymmetries in confinement and that topological and chemical cues may be encoded differently by cells. Overall, our ratchet channels could mimic small blood vessels in which cells such as circulating tumor cells are confined; cells can probe local asymmetries that determine their entry into tissues and their subsequent direction. Our results shed light on invasion mechanisms in cancer.
    DOI:  https://doi.org/10.1016/j.bpj.2020.08.028
  73. Front Physiol. 2020 ;11 567881
    Muscle-Organ Crosstalk: Focus on Immunometabolism.
    Marie Lund Bay, Bente Klarlund Pedersen.
      Skeletal muscle secretes several hundred myokines that facilitate communication from muscle to other organs, such as, adipose tissue, pancreas, liver, gut, and brain. The biological roles of myokines include effects on e.g., memory and learning, as well as glucose and lipid metabolism. The present minireview focuses on recent developments showing that exercise-induced myokines are involved in immunometabolism of importance for the control of e.g., tumor growth and chronic inflammation. In this review, immunometabolism is discussed as the non-immune related pathologies leading to an immune response and some degree of inflammation, which promotes metabolic abnormalities.
    Keywords:  cancer; cytokines; diabetes; exercise; metabolism; physical activity
    DOI:  https://doi.org/10.3389/fphys.2020.567881
  74. Nat Biomed Eng. 2020 Oct 05.
    Design and clinical implementation of an open-source bionic leg.
    Alejandro F Azocar, Luke M Mooney, Jean-François Duval, Ann M Simon, Levi J Hargrove, Elliott J Rouse.
      In individuals with lower-limb amputations, robotic prostheses can increase walking speed, and reduce energy use, the incidence of falls and the development of secondary complications. However, safe and reliable prosthetic-limb control strategies for robust ambulation in real-world settings remain out of reach, partly because control strategies have been tested with different robotic hardware in constrained laboratory settings. Here, we report the design and clinical implementation of an integrated robotic knee-ankle prosthesis that facilitates the real-world testing of its biomechanics and control strategies. The bionic leg is open source, it includes software for low-level control and for communication with control systems, and its hardware design is customizable, enabling reduction in its mass and cost, improvement in its ease of use and independent operation of the knee and ankle joints. We characterized the electromechanical and thermal performance of the bionic leg in benchtop testing, as well as its kinematics and kinetics in three individuals during walking on level ground, ramps and stairs. The open-source integrated-hardware solution and benchmark data that we provide should help with research and clinical testing of knee-ankle prostheses in real-world environments.
    DOI:  https://doi.org/10.1038/s41551-020-00619-3
  75. Sci Adv. 2020 Oct;pii: eabc7120. [Epub ahead of print]6(41):
    Dietary thiamine influences l-asparaginase sensitivity in a subset of leukemia cells.
    Rohiverth Guarecuco, Robert T Williams, Lou Baudrier, Konnor La, Maria C Passarelli, Naz Ekizoglu, Mert Mestanoglu, Hanan Alwaseem, Bety Rostandy, Justine Fidelin, Javier Garcia-Bermudez, Henrik Molina, Kıvanç Birsoy.
      Tumor environment influences anticancer therapy response but which extracellular nutrients affect drug sensitivity is largely unknown. Using functional genomics, we determine modifiers of l-asparaginase (ASNase) response and identify thiamine pyrophosphate kinase 1 as a metabolic dependency under ASNase treatment. While thiamine is generally not limiting for cell proliferation, a DNA-barcode competition assay identifies leukemia cell lines that grow suboptimally under low thiamine and are characterized by low expression of solute carrier family 19 member 2 (SLC19A2), a thiamine transporter. SLC19A2 is necessary for optimal growth and ASNase resistance, when standard medium thiamine is lowered ~100-fold to human plasma concentrations. In addition, humanizing blood thiamine content of mice through diet sensitizes SLC19A2-low leukemia cells to ASNase in vivo. Together, our work reveals that thiamine utilization is a determinant of ASNase response for some cancer cells and that oversupplying vitamins may affect therapeutic response in leukemia.
    DOI:  https://doi.org/10.1126/sciadv.abc7120
  76. Nat Biotechnol. 2020 Oct;38(10): 1121-1122
    Top 20 translational researchers of 2019.
    Brady Huggett, Kathryn Paisner.
      
    DOI:  https://doi.org/10.1038/s41587-020-0680-3
  77. Nature. 2020 Oct 05.
    Virologists who discovered hepatitis C win medicine Nobel.
    Ewen Callaway, Heidi Ledford.
      
    Keywords:  Virology
    DOI:  https://doi.org/10.1038/d41586-020-02763-x
  78. Medicina (Kaunas). 2020 Oct 07. pii: E523. [Epub ahead of print]56(10):
    State of the Art in Exocrine Pancreatic Insufficiency.
    Carmelo Diéguez-Castillo, Cristina Jiménez-Luna, Jose Prados, José Luis Martín-Ruiz, Octavio Caba.
      Exocrine pancreatic insufficiency (EPI) is defined as the maldigestion of foods due to inadequate pancreatic secretion, which can be caused by alterations in its stimulation, production, transport, or interaction with nutrients at duodenal level. The most frequent causes are chronic pancreatitis in adults and cystic fibrosis in children. The prevalence of EPI is high, varying according to its etiology, but it is considered to be underdiagnosed and undertreated. Its importance lies in the quality of life impairment that results from the malabsorption and malnutrition and in the increased morbidity and mortality, being associated with osteoporosis and cardiovascular events. The diagnosis is based on a set of symptoms, indicators of malnutrition, and an indirect non-invasive test in at-risk patients. The treatment of choice combines non-restrictive dietary measures with pancreatic enzyme replacement therapy to correct the associated symptoms and improve the nutritional status of patients. Non-responders require the adjustment of pancreatic enzyme therapy, the association of proton pump inhibitors, and/or the evaluation of alternative diagnoses such as bacterial overgrowth. This review offers an in-depth overview of EPI in order to support the proper management of this entity based on updated and integrated knowledge of its etiopathogenesis, prevalence, diagnosis, and treatment.
    Keywords:  clinic relevance; diagnosis; exocrine pancreatic insufficiency; pancreatic enzyme replacement therapy; prevalence; treatment
    DOI:  https://doi.org/10.3390/medicina56100523
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