bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2020–05–31
forty-five papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Selective autophagy of MHC-I promotes immune evasion of pancreatic cancer.
  2. Lipidomic atlas of mammalian cell membranes reveals hierarchical variation induced by culture conditions, subcellular membranes, and cell lineages.
  3. Phase and context shape the function of composite oncogenic mutations.
  4. Tumour predisposition and cancer syndromes as models to study gene-environment interactions.
  5. High-content fluorescence imaging with the metabolic flux assay reveals insights into mitochondrial properties and functions.
  6. ISG15 and ISGylation is required for pancreatic cancer stem cell mitophagy and metabolic plasticity.
  7. Differential contribution of pancreatic fibroblast subsets to the pancreatic cancer stroma.
  8. Studies on the mechanism of general anesthesia.
  9. CXCR2 signaling promotes secretory cancer-associated fibroblasts in pancreatic ductal adenocarcinoma.
  10. BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer: the COMBAT trial.
  11. Distinct mitochondrial defects trigger the integrated stress response depending on the metabolic state of the cell.
  12. Systemic dysfunction and plasticity of the immune macroenvironment in cancer models.
  13. Bacterial metabolism of bile acids promotes generation of peripheral regulatory T cells.
  14. Systemic effects of mitochondrial stress.
  15. Interrogation of the Microenvironmental Landscape in Brain Tumors Reveals Disease-Specific Alterations of Immune Cells.
  16. Extracellular serine controls epidermal stem cell fate and tumour initiation.
  17. The human tumor microbiome is composed of tumor type-specific intracellular bacteria.
  18. Intraductal pancreatic cancer is less responsive than cancer in the stroma to neoadjuvant chemotherapy.
  19. Signal transducer and activator of transcription 5a (STAT5a) represses mitochondrial gene expression through direct binding to mitochondrial DNA.
  20. Cryo-EM structures provide insight into how E. coli F1Fo ATP synthase accommodates symmetry mismatch.
  21. The quest to slow ageing through drug discovery.
  22. DIVERSITY AND BIOLOGY OF CANCER-ASSOCIATED FIBROBLASTS.
  23. Perturbation-Driven Entropy as a Source of Cancer Cell Heterogeneity.
  24. The extracellular matrix in development.
  25. Lipid remodelling in hepatocyte proliferation and hepatocellular carcinoma.
  26. Tunneling Nanotubes: The Fuel of Tumor Progression?
  27. Molecular Choreography of Acute Exercise.
  28. Myeloma cells shift osteoblastogenesis to adipogenesis by inhibiting the ubiquitin ligase MURF1 in mesenchymal stem cells.
  29. Take lessons from cancer evolution to the clinic.
  30. MAX Functions as a Tumor Suppressor and Rewires Metabolism in Small Cell Lung Cancer.
  31. Type 1 conventional dendritic cells are systemically dysregulated early in pancreatic carcinogenesis.
  32. TORC1 inactivation stimulates autophagy of nucleoporin and nuclear pore complexes.
  33. Unravelling novel weight loss mechanisms.
  34. Biomarker-Guided Development of DNA Repair Inhibitors.
  35. Tumour Cell Secretome in Chemoresistance and Tumour Recurrence.
  36. Cerebrovascular reactivity: a new frontier for measuring cognitive health in models of accelerated aging?
  37. Reducing transmission of SARS-CoV-2.
  38. IGF-1 receptor activity in the Golgi of migratory cancer cells depends on adhesion-dependent phosphorylation of Tyr1250 and Tyr1251.
  39. Limitation of adipose tissue by the number of embryonic progenitor cells.
  40. Human ESCRT-III polymers assemble on positively curved membranes and induce helical membrane tube formation.
  41. Protein Phase Separation during Stress Adaptation and Cellular Memory.
  42. TORC1 signaling regulates cytoplasmic pH through Sir2 in yeast.
  43. Coupling of Ribosome Synthesis and Translational Capacity with Cell Growth.
  44. Investigating cell cycle-dependent gene expression in the context of nuclear architecture at a single allele resolution.
  45. The Mitochondria-Associated ER Membranes Are Novel Subcellular Locations Enriched for Inflammatory-Responsive MicroRNAs.
  1. Autophagy. 2020 May 27. 1-2
    Selective autophagy of MHC-I promotes immune evasion of pancreatic cancer.
    Keisuke Yamamoto, Anthony Venida, Rushika M Perera, Alec C Kimmelman.
      Major histocompatibility complex class I (MHC-I) is a key molecule in anti-tumor adaptive immunity. MHC-I is essential for endogenous antigen presentation by cancer cells and subsequent recognition and clearance by CD8+ T cells. Defects in MHC-I expression occur frequently in several cancers, leading to impaired antigen presentation, immune evasion and/or resistance to immune checkpoint blockade (ICB) therapy. Pancreatic ductal adenocarcinoma (PDAC), a deadly malignancy with dismal patient prognosis, is resistant to ICB and shows frequent downregulation of MHC-I independent of genetic mutations abrogating MHC-I expression. Previously, we showed that PDAC cells exhibit elevated levels of autophagy and lysosomal biogenesis, which together support the survival and growth of PDAC tumors via both cell-autonomous and non-cell-autonomous mechanisms. In our recent study, we have identified NBR1-mediated selective macroautophagy/autophagy of MHC-I as a novel mechanism that facilitates immune evasion by PDAC cells. Importantly, autophagy or lysosome inhibition restores MHC-I expression, leading to enhanced anti-tumor T cell immunity and improved response to ICB in transplanted tumor models in syngeneic host mice. Our results highlight a previously unknown function of autophagy and the lysosome in regulation of immunogenicity in PDAC, and provide a novel therapeutic strategy for targeting this deadly disease.
    Keywords:  MHC-I; Pancreatic cancer; anti-tumor immunity; autophagy; immune checkpoint blockade; lysosome
    DOI:  https://doi.org/10.1080/15548627.2020.1769973
  2. Soft Matter. 2020 May 26.
    Lipidomic atlas of mammalian cell membranes reveals hierarchical variation induced by culture conditions, subcellular membranes, and cell lineages.
    Jessica L Symons, Kwang-Jin Cho, Jeffrey T Chang, Guangwei Du, M Neal Waxham, John F Hancock, Ilya Levental, Kandice R Levental.
      Lipid membranes are ubiquitous biological organizers, required for structural and functional compartmentalization of the cell and sub-cellular organelles. Membranes in living cells are compositionally complex, comprising hundreds of dynamically regulated, distinct lipid species. Cellular physiology requires tight regulation of these lipidomic profiles to achieve proper membrane functionality. While some general features of tissue- and organelle-specific lipid complements have been identified, less is known about detailed lipidomic variations caused by cell-intrinsic or extrinsic factors. Here, we use shotgun lipidomics to report detailed, comprehensive lipidomes of a variety of cultured and primary mammalian membrane preparations to identify trends and sources of variation. Unbiased principle component analysis (PCA) shows clear separation between cultured and primary cells, with primary erythrocytes, synaptic membranes, and other mammalian tissue lipidomes sharply diverging from all cultured cell lines and also from one other. Most broadly, cultured cell membrane preparations were distinguished by their paucity of polyunsaturated lipids. Cultured mammalian cell lines were comparatively similar to one another, although we detected clear, highly reproducible lipidomic signatures of individual cell lines and plasma membrane (PM) isolations thereof. These measurements begin to establish a comprehensive lipidomic atlas of mammalian cells and tissues, identifying some major sources of variation. These observations will allow investigation of the regulation and functional significance of mammalian lipidomes in various contexts.
    DOI:  https://doi.org/10.1039/d0sm00404a
  3. Nature. 2020 May 27.
    Phase and context shape the function of composite oncogenic mutations.
    Alexander N Gorelick, Francisco J Sánchez-Rivera, Yanyan Cai, Craig M Bielski, Evan Biederstedt, Philip Jonsson, Allison L Richards, Neil Vasan, Alexander V Penson, Noah D Friedman, Yu-Jui Ho, Timour Baslan, Chaitanya Bandlamudi, Maurizio Scaltriti, Nikolaus Schultz, Scott W Lowe, Ed Reznik, Barry S Taylor.
      Cancers develop as a result of driver mutations1,2 that lead to clonal outgrowth and the evolution of disease3,4. The discovery and functional characterization of individual driver mutations are central aims of cancer research, and have elucidated myriad phenotypes5 and therapeutic vulnerabilities6. However, the serial genetic evolution of mutant cancer genes7,8 and the allelic context in which they arise is poorly understood in both common and rare cancer genes and tumour types. Here we find that nearly one in four human tumours contains a composite mutation of a cancer-associated gene, defined as two or more nonsynonymous somatic mutations in the same gene and tumour. Composite mutations are enriched in specific genes, have an elevated rate of use of less-common hotspot mutations acquired in a chronology driven in part by oncogenic fitness, and arise in an allelic configuration that reflects context-specific selective pressures. cis-acting composite mutations are hypermorphic in some genes in which dosage effects predominate (such as TERT), whereas they lead to selection of function in other genes (such as TP53). Collectively, composite mutations are driver alterations that arise from context- and allele-specific selective pressures that are dependent in part on gene and mutation function, and which lead to complex-often neomorphic-functions of biological and therapeutic importance.
    DOI:  https://doi.org/10.1038/s41586-020-2315-8
  4. Nat Rev Cancer. 2020 May 29.
    Tumour predisposition and cancer syndromes as models to study gene-environment interactions.
    Michele Carbone, Sarah T Arron, Bruce Beutler, Angela Bononi, Webster Cavenee, James E Cleaver, Carlo M Croce, Alan D'Andrea, William D Foulkes, Giovanni Gaudino, Joanna L Groden, Elizabeth P Henske, Ian D Hickson, Paul M Hwang, Richard D Kolodner, Tak W Mak, David Malkin, Raymond J Monnat, Flavia Novelli, Harvey I Pass, John H Petrini, Laura S Schmidt, Haining Yang.
      Cell division and organismal development are exquisitely orchestrated and regulated processes. The dysregulation of the molecular mechanisms underlying these processes may cause cancer, a consequence of cell-intrinsic and/or cell-extrinsic events. Cellular DNA can be damaged by spontaneous hydrolysis, reactive oxygen species, aberrant cellular metabolism or other perturbations that cause DNA damage. Moreover, several environmental factors may damage the DNA, alter cellular metabolism or affect the ability of cells to interact with their microenvironment. While some environmental factors are well established as carcinogens, there remains a large knowledge gap of others owing to the difficulty in identifying them because of the typically long interval between carcinogen exposure and cancer diagnosis. DNA damage increases in cells harbouring mutations that impair their ability to correctly repair the DNA. Tumour predisposition syndromes in which cancers arise at an accelerated rate and in different organs - the equivalent of a sensitized background - provide a unique opportunity to examine how gene-environment interactions influence cancer risk when the initiating genetic defect responsible for malignancy is known. Understanding the molecular processes that are altered by specific germline mutations, environmental exposures and related mechanisms that promote cancer will allow the design of novel and effective preventive and therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41568-020-0265-y
  5. Commun Biol. 2020 May 29. 3(1): 271
    High-content fluorescence imaging with the metabolic flux assay reveals insights into mitochondrial properties and functions.
    Andrew Charles Little, Ilya Kovalenko, Laura Elaine Goo, Hanna Sungok Hong, Samuel Andrew Kerk, Joel Anthony Yates, Vinee Purohit, David Benner Lombard, Sofia Diana Merajver, Costas Andreas Lyssiotis.
      Metabolic flux technology with the Seahorse bioanalyzer has emerged as a standard technique in cellular metabolism studies, allowing for simultaneous kinetic measurements of respiration and glycolysis. Methods to extend the utility and versatility of the metabolic flux assay would undoubtedly have immediate and wide-reaching impacts. Herein, we describe a platform that couples the metabolic flux assay with high-content fluorescence imaging to simultaneously provide means for normalization of respiration data with cell number; analyze cell cycle distribution; and quantify mitochondrial content, fragmentation state, membrane potential, and mitochondrial reactive oxygen species. Integration of fluorescent dyes directly into the metabolic flux assay generates a more complete data set of mitochondrial features in a single assay. Moreover, application of this integrated strategy revealed insights into mitochondrial function following PGC1a and PRC1 inhibition in pancreatic cancer and demonstrated how the Rho-GTPases impact mitochondrial dynamics in breast cancer.
    DOI:  https://doi.org/10.1038/s42003-020-0988-z
  6. Nat Commun. 2020 May 29. 11(1): 2682
    ISG15 and ISGylation is required for pancreatic cancer stem cell mitophagy and metabolic plasticity.
    Sonia Alcalá, Patricia Sancho, Paola Martinelli, Diego Navarro, Coral Pedrero, Laura Martín-Hijano, Sandra Valle, Julie Earl, Macarena Rodríguez-Serrano, Laura Ruiz-Cañas, Katerin Rojas, Alfredo Carrato, Laura García-Bermejo, Miguel Ángel Fernández-Moreno, Patrick C Hermann, Bruno Sainz.
      Pancreatic cancer stem cells (PaCSCs) drive pancreatic cancer tumorigenesis, chemoresistance and metastasis. While eliminating this subpopulation of cells would theoretically result in tumor eradication, PaCSCs are extremely plastic and can successfully adapt to targeted therapies. In this study, we demonstrate that PaCSCs increase expression of interferon-stimulated gene 15 (ISG15) and protein ISGylation, which are essential for maintaining their metabolic plasticity. CRISPR-mediated ISG15 genomic editing reduces overall ISGylation, impairing PaCSCs self-renewal and their in vivo tumorigenic capacity. At the molecular level, ISG15 loss results in decreased mitochondrial ISGylation concomitant with increased accumulation of dysfunctional mitochondria, reduced oxidative phosphorylation (OXPHOS) and impaired mitophagy. Importantly, disruption in mitochondrial metabolism affects PaCSC metabolic plasticity, making them susceptible to prolonged inhibition with metformin in vivo. Thus, ISGylation is critical for optimal and efficient OXPHOS by ensuring the recycling of dysfunctional mitochondria, and when absent, a dysregulation in mitophagy occurs that negatively impacts PaCSC stemness.
    DOI:  https://doi.org/10.1038/s41467-020-16395-2
  7. Cell Mol Gastroenterol Hepatol. 2020 May 23. pii: S2352-345X(20)30074-6. [Epub ahead of print]
    Differential contribution of pancreatic fibroblast subsets to the pancreatic cancer stroma.
    Paloma E Garcia, Maeva Adoumie, Esther C Kim, Yaqing Zhang, Michael K Scales, Yara S El-Tawil, Amara Z Shaikh, Hui-Ju Wen, Filip Bednar, Ben L Allen, Deneen M Wellik, Howard C Crawford, Marina Pasca di Magliano.
       BACKGROUND & AIMS: While the healthy pancreas consists mostly of epithelial cells, pancreatic cancer and the precursor lesions known as PanINs, are characterized by an extensive accumulation of fibroinflammatory stroma that includes a substantial and heterogeneous fibroblast population. The cellular origin of fibroblasts within the stroma has not been determined. Here, we show that the Gli1 and Hoxb6 markers label distinct fibroblast populations in the healthy mouse pancreas. We then set out to determine whether these distinct fibroblast populations expanded during carcinogenesis.
    METHODS: We developed genetically engineered models using a dual-recombinase approach that allowed us to induce pancreatic cancer formation through FlpO-driven epithelial recombination of Kras while labelling Gli1+ or Hoxb6+ fibroblasts in an inducible manner. Using these models, we lineage-traced these two fibroblast populations during the process of carcinogenesis.
    RESULTS: While in the healthy pancreas Gli1+ fibroblasts and Hoxb6+ fibroblasts are present in similar numbers; they contribute differently to the stroma in carcinogenesis. Namely, Gli1+ fibroblasts dramatically expand, while Hoxb6+ cells do not.
    CONCLUSIONS: Fibroblasts present in the healthy pancreas expand during carcinogenesis, but with different prevalence for different subtypes. Here, we compared Gli1+ and Hoxb6+ fibroblasts and found only Gli1+ expanded to contribute to the stroma during pancreatic carcinogenesis.
    Keywords:  Cancer-associated fibroblasts (CAFs); Gli1; heterogeneity; lineage-trace; pancreas
    DOI:  https://doi.org/10.1016/j.jcmgh.2020.05.004
  8. Proc Natl Acad Sci U S A. 2020 May 28. pii: 202004259. [Epub ahead of print]
    Studies on the mechanism of general anesthesia.
    Mahmud Arif Pavel, E Nicholas Petersen, Hao Wang, Richard A Lerner, Scott B Hansen.
      Inhaled anesthetics are a chemically diverse collection of hydrophobic molecules that robustly activate TWIK-related K+ channels (TREK-1) and reversibly induce loss of consciousness. For 100 y, anesthetics were speculated to target cellular membranes, yet no plausible mechanism emerged to explain a membrane effect on ion channels. Here we show that inhaled anesthetics (chloroform and isoflurane) activate TREK-1 through disruption of phospholipase D2 (PLD2) localization to lipid rafts and subsequent production of signaling lipid phosphatidic acid (PA). Catalytically dead PLD2 robustly blocks anesthetic TREK-1 currents in whole-cell patch-clamp recordings. Localization of PLD2 renders the TRAAK channel sensitive, a channel that is otherwise anesthetic insensitive. General anesthetics, such as chloroform, isoflurane, diethyl ether, xenon, and propofol, disrupt lipid rafts and activate PLD2. In the whole brain of flies, anesthesia disrupts rafts and PLDnull flies resist anesthesia. Our results establish a membrane-mediated target of inhaled anesthesia and suggest PA helps set thresholds of anesthetic sensitivity in vivo.
    Keywords:  consciousness; lipid raft; phospholipase D; potassium channel; substrate presentation
    DOI:  https://doi.org/10.1073/pnas.2004259117
  9. FASEB J. 2020 May 26.
    CXCR2 signaling promotes secretory cancer-associated fibroblasts in pancreatic ductal adenocarcinoma.
    Mohammad Awaji, Sugandha Saxena, Lingyun Wu, Dipakkumar R Prajapati, Abhilasha Purohit, Michelle L Varney, Sushil Kumar, Satyanarayana Rachagani, Quan P Ly, Maneesh Jain, Surinder K Batra, Rakesh K Singh.
      Pancreatic ductal adenocarcinoma (PDAC) remains one of the most challenging malignancies. Desmoplasia and tumor-supporting inflammation are hallmarks of PDAC. The tumor microenvironment contributes significantly to tumor progression and spread. Cancer-associated fibroblasts (CAFs) facilitate therapy resistance and metastasis. Recent reports emphasized the concurrence of multiple subtypes of CAFs with diverse roles, fibrogenic, and secretory. C-X-C motif chemokine receptor 2 (CXCR2) is a chemokine receptor known for its role during inflammation and its adverse role in PDAC. Oncogenic Kras upregulates CXCR2 and its ligands and, thus, contribute to tumor proliferation and immunosuppression. CXCR2 deletion in a PDAC syngeneic mouse model produced increased fibrosis revealing a potential undescribed role of CXCR2 in CAFs. In this study, we demonstrate that the oncogenic Kras-CXCR2 axis regulates the CAFs function in PDAC and contributes to CAFs heterogeneity. We observed that oncogenic Kras and CXCR2 signaling alter CAFs, producing a secretory CAF phenotype with low fibrogenic features; and increased secretion of pro-tumor cytokines and CXCR2 ligands, utilizing the NF-κB activity. Finally, using syngeneic mouse models, we demonstrate that oncogenic Kras is associated with secretory CAFs and that CXCR2 inhibition promotes activation of fibrotic cells (myofibroblasts) and impact tumors in a mutation-dependent manner.
    Keywords:  CAFs; chemokines; desmoplasia; inflammation; oncogenic Kras
    DOI:  https://doi.org/10.1096/fj.201902990R
  10. Nat Med. 2020 May 25.
    BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer: the COMBAT trial.
    Bruno Bockorny, Valerya Semenisty, Teresa Macarulla, Erkut Borazanci, Brian M Wolpin, Salomon M Stemmer, Talia Golan, Ravit Geva, Mitesh J Borad, Katrina S Pedersen, Joon Oh Park, Robert A Ramirez, David G Abad, Jaime Feliu, Andres Muñoz, Mariano Ponz-Sarvise, Amnon Peled, Tzipora M Lustig, Osnat Bohana-Kashtan, Stephen M Shaw, Ella Sorani, Marya Chaney, Shaul Kadosh, Abi Vainstein Haras, Daniel D Von Hoff, Manuel Hidalgo.
      Programmed cell death 1 (PD-1) inhibitors have limited effect in pancreatic ductal adenocarcinoma (PDAC), underscoring the need to co-target alternative pathways. CXC chemokine receptor 4 (CXCR4) blockade promotes T cell tumor infiltration and is synergistic with anti-PD-1 therapy in PDAC mouse models. We conducted a phase IIa, open-label, two-cohort study to assess the safety, efficacy and immunobiological effects of the CXCR4 antagonist BL-8040 (motixafortide) with pembrolizumab and chemotherapy in metastatic PDAC (NCT02826486). The primary outcome was objective response rate (ORR). Secondary outcomes were overall survival (OS), disease control rate (DCR) and safety. In cohort 1, 37 patients with chemotherapy-resistant disease received BL-8040 and pembrolizumab. The DCR was 34.5% in the evaluable population (modified intention to treat, mITT; N = 29), including nine patients (31%) with stable disease and one patient (3.4%) with partial response. Median OS (mOS) was 3.3 months in the ITT population. Notably, in patients receiving study drugs as second-line therapy, the mOS was 7.5 months. BL-8040 increased CD8+ effector T cell tumor infiltration, decreased myeloid-derived suppressor cells (MDSCs) and further decreased circulating regulatory T cells. In cohort 2, 22 patients received BL-8040 and pembrolizumab with chemotherapy, with an ORR, DCR and median duration of response of 32%, 77% and 7.8 months, respectively. These data suggest that combined CXCR4 and PD-1 blockade may expand the benefit of chemotherapy in PDAC and warrants confirmation in subsequent randomized trials.
    DOI:  https://doi.org/10.1038/s41591-020-0880-x
  11. Elife. 2020 May 28. pii: e49178. [Epub ahead of print]9
    Distinct mitochondrial defects trigger the integrated stress response depending on the metabolic state of the cell.
    Eran Mick, Denis V Titov, Owen S Skinner, Rohit Sharma, Alexis A Jourdain, Vamsi K Mootha.
      Mitochondrial dysfunction is associated with activation of the integrated stress response (ISR) but the underlying triggers remain unclear. We systematically combined acute mitochondrial inhibitors with genetic tools for compartment-specific NADH oxidation to trace mechanisms linking different forms of mitochondrial dysfunction to the ISR in proliferating mouse myoblasts and in differentiated myotubes. In myoblasts, we find that impaired NADH oxidation upon electron transport chain (ETC) inhibition depletes asparagine, activating the ISR via the eIF2α kinase GCN2. In myotubes, however, impaired NADH oxidation following ETC inhibition neither depletes asparagine nor activates the ISR, reflecting an altered metabolic state. ATP synthase inhibition in myotubes triggers the ISR via a distinct mechanism related to mitochondrial inner-membrane hyperpolarization. Our work dispels the notion of a universal path linking mitochondrial dysfunction to the ISR, instead revealing multiple paths that depend both on the nature of the mitochondrial defect and on the metabolic state of the cell.
    Keywords:  ATF4; GCN2; genetics; genomics; human; human biology; integrated stress response; medicine; metabolism; mitochondria; mouse; p53
    DOI:  https://doi.org/10.7554/eLife.49178
  12. Nat Med. 2020 May 25.
    Systemic dysfunction and plasticity of the immune macroenvironment in cancer models.
    Breanna M Allen, Kamir J Hiam, Cassandra E Burnett, Anthony Venida, Rachel DeBarge, Iliana Tenvooren, Diana M Marquez, Nam Woo Cho, Yaron Carmi, Matthew H Spitzer.
      Understanding of the factors governing immune responses in cancer remains incomplete, limiting patient benefit. In this study, we used mass cytometry to define the systemic immune landscape in response to tumor development across five tissues in eight mouse tumor models. Systemic immunity was dramatically altered across models and time, with consistent findings in the peripheral blood of patients with breast cancer. Changes in peripheral tissues differed from those in the tumor microenvironment. Mice with tumor-experienced immune systems mounted dampened responses to orthogonal challenges, including reduced T cell activation during viral or bacterial infection. Antigen-presenting cells (APCs) mounted weaker responses in this context, whereas promoting APC activation rescued T cell activity. Systemic immune changes were reversed with surgical tumor resection, and many were prevented by interleukin-1 or granulocyte colony-stimulating factor blockade, revealing remarkable plasticity in the systemic immune state. These results demonstrate that tumor development dynamically reshapes the composition and function of the immune macroenvironment.
    DOI:  https://doi.org/10.1038/s41591-020-0892-6
  13. Nature. 2020 May;581(7809): 475-479
    Bacterial metabolism of bile acids promotes generation of peripheral regulatory T cells.
    Clarissa Campbell, Peter T McKenney, Daniel Konstantinovsky, Olga I Isaeva, Michail Schizas, Jacob Verter, Cheryl Mai, Wen-Bing Jin, Chun-Jun Guo, Sara Violante, Ruben J Ramos, Justin R Cross, Krishna Kadaveru, John Hambor, Alexander Y Rudensky.
      Intestinal health relies on the immunosuppressive activity of CD4+ regulatory T (Treg) cells1. Expression of the transcription factor Foxp3 defines this lineage, and can be induced extrathymically by dietary or commensal-derived antigens in a process assisted by a Foxp3 enhancer known as conserved non-coding sequence 1 (CNS1)2-4. Products of microbial fermentation including butyrate facilitate the generation of peripherally induced Treg (pTreg) cells5-7, indicating that metabolites shape the composition of the colonic immune cell population. In addition to dietary components, bacteria modify host-derived molecules, generating a number of biologically active substances. This is epitomized by the bacterial transformation of bile acids, which creates a complex pool of steroids8 with a range of physiological functions9. Here we screened the major species of deconjugated bile acids for their ability to potentiate the differentiation of pTreg cells. We found that the secondary bile acid 3β-hydroxydeoxycholic acid (isoDCA) increased Foxp3 induction by acting on dendritic cells (DCs) to diminish their immunostimulatory properties. Ablating one receptor, the farnesoid X receptor, in DCs enhanced the generation of Treg cells and imposed a transcriptional profile similar to that induced by isoDCA, suggesting an interaction between this bile acid and nuclear receptor. To investigate isoDCA in vivo, we took a synthetic biology approach and designed minimal microbial consortia containing engineered Bacteroides strains. IsoDCA-producing consortia increased the number of colonic RORγt-expressing Treg cells in a CNS1-dependent manner, suggesting enhanced extrathymic differentiation.
    DOI:  https://doi.org/10.1038/s41586-020-2193-0
  14. EMBO Rep. 2020 May 24. e50094
    Systemic effects of mitochondrial stress.
    Raz Bar-Ziv, Theodore Bolas, Andrew Dillin.
      Multicellular organisms are complex biological systems, composed of specialized tissues that require coordination of the metabolic and fitness state of each component. In the cells composing the tissues, one central organelle is the mitochondrion, a compartment essential for many energetic and fundamental biological processes. Beyond serving these functions, mitochondria have emerged as signaling hubs in biological systems, capable of inducing changes to the cell they are in, to cells in distal tissues through secreted factors, and to overall animal physiology. Here, we describe our current understanding of these communication mechanisms in the context of mitochondrial stress. We focus on cellular mechanisms that deal with perturbations to the mitochondrial proteome and outline recent advances in understanding how local perturbations can affect distal tissues and animal physiology in model organisms. Finally, we discuss recent findings of these responses associated with metabolic and age-associated diseases in mammalian systems, and how they may be employed as diagnostic and therapeutic tools.
    Keywords:  aging; mitochondria; stress
    DOI:  https://doi.org/10.15252/embr.202050094
  15. Cell. 2020 May 23. pii: S0092-8674(20)30569-9. [Epub ahead of print]
    Interrogation of the Microenvironmental Landscape in Brain Tumors Reveals Disease-Specific Alterations of Immune Cells.
    Florian Klemm, Roeltje R Maas, Robert L Bowman, Mara Kornete, Klara Soukup, Sina Nassiri, Jean-Philippe Brouland, Christine A Iacobuzio-Donahue, Cameron Brennan, Viviane Tabar, Philip H Gutin, Roy T Daniel, Monika E Hegi, Johanna A Joyce.
      Brain malignancies encompass a range of primary and metastatic cancers, including low-grade and high-grade gliomas and brain metastases (BrMs) originating from diverse extracranial tumors. Our understanding of the brain tumor microenvironment (TME) remains limited, and it is unknown whether it is sculpted differentially by primary versus metastatic disease. We therefore comprehensively analyzed the brain TME landscape via flow cytometry, RNA sequencing, protein arrays, culture assays, and spatial tissue characterization. This revealed disease-specific enrichment of immune cells with pronounced differences in proportional abundance of tissue-resident microglia, infiltrating monocyte-derived macrophages, neutrophils, and T cells. These integrated analyses also uncovered multifaceted immune cell activation within brain malignancies entailing converging transcriptional trajectories while maintaining disease- and cell-type-specific programs. Given the interest in developing TME-targeted therapies for brain malignancies, this comprehensive resource of the immune landscape offers insights into possible strategies to overcome tumor-supporting TME properties and instead harness the TME to fight cancer.
    Keywords:  T cells; brain metastasis; cancer immunology; glioblastoma; glioma; microglia; monocyte-derived macrophages; neutrophils; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.cell.2020.05.007
  16. Nat Cell Biol. 2020 May 25.
    Extracellular serine controls epidermal stem cell fate and tumour initiation.
    Sanjeethan C Baksh, Pavlina K Todorova, Shiri Gur-Cohen, Brian Hurwitz, Yejing Ge, Jesse S S Novak, Matthew T Tierney, June Dela Cruz-Racelis, Elaine Fuchs, Lydia W S Finley.
      Tissue stem cells are the cell of origin for many malignancies. Metabolites regulate the balance between self-renewal and differentiation, but whether endogenous metabolic pathways or nutrient availability predispose stem cells towards transformation remains unknown. Here, we address this question in epidermal stem cells (EpdSCs), which are a cell of origin for squamous cell carcinoma. We find that oncogenic EpdSCs are serine auxotrophs whose growth and self-renewal require abundant exogenous serine. When extracellular serine is limited, EpdSCs activate de novo serine synthesis, which in turn stimulates α-ketoglutarate-dependent dioxygenases that remove the repressive histone modification H3K27me3 and activate differentiation programmes. Accordingly, serine starvation or enforced α-ketoglutarate production antagonizes squamous cell carcinoma growth. Conversely, blocking serine synthesis or repressing α-ketoglutarate-driven demethylation facilitates malignant progression. Together, these findings reveal that extracellular serine is a critical determinant of EpdSC fate and provide insight into how nutrient availability is integrated with stem cell fate decisions during tumour initiation.
    DOI:  https://doi.org/10.1038/s41556-020-0525-9
  17. Science. 2020 May 29. 368(6494): 973-980
    The human tumor microbiome is composed of tumor type-specific intracellular bacteria.
    Deborah Nejman, Ilana Livyatan, Garold Fuks, Nancy Gavert, Yaara Zwang, Leore T Geller, Aviva Rotter-Maskowitz, Roi Weiser, Giuseppe Mallel, Elinor Gigi, Arnon Meltser, Gavin M Douglas, Iris Kamer, Vancheswaran Gopalakrishnan, Tali Dadosh, Smadar Levin-Zaidman, Sofia Avnet, Tehila Atlan, Zachary A Cooper, Reetakshi Arora, Alexandria P Cogdill, Md Abdul Wadud Khan, Gabriel Ologun, Yuval Bussi, Adina Weinberger, Maya Lotan-Pompan, Ofra Golani, Gili Perry, Merav Rokah, Keren Bahar-Shany, Elisa A Rozeman, Christian U Blank, Anat Ronai, Ron Shaoul, Amnon Amit, Tatiana Dorfman, Ran Kremer, Zvi R Cohen, Sagi Harnof, Tali Siegal, Einav Yehuda-Shnaidman, Einav Nili Gal-Yam, Hagit Shapira, Nicola Baldini, Morgan G I Langille, Alon Ben-Nun, Bella Kaufman, Aviram Nissan, Talia Golan, Maya Dadiani, Keren Levanon, Jair Bar, Shlomit Yust-Katz, Iris Barshack, Daniel S Peeper, Dan J Raz, Eran Segal, Jennifer A Wargo, Judith Sandbank, Noam Shental, Ravid Straussman.
      Bacteria were first detected in human tumors more than 100 years ago, but the characterization of the tumor microbiome has remained challenging because of its low biomass. We undertook a comprehensive analysis of the tumor microbiome, studying 1526 tumors and their adjacent normal tissues across seven cancer types, including breast, lung, ovary, pancreas, melanoma, bone, and brain tumors. We found that each tumor type has a distinct microbiome composition and that breast cancer has a particularly rich and diverse microbiome. The intratumor bacteria are mostly intracellular and are present in both cancer and immune cells. We also noted correlations between intratumor bacteria or their predicted functions with tumor types and subtypes, patients' smoking status, and the response to immunotherapy.
    DOI:  https://doi.org/10.1126/science.aay9189
  18. Mod Pathol. 2020 May 26.
    Intraductal pancreatic cancer is less responsive than cancer in the stroma to neoadjuvant chemotherapy.
    Kohei Fujikura, Danielle Hutchings, Alicia M Braxton, Qingfeng Zhu, Daniel A Laheru, Ralph H Hruban, Elizabeth D Thompson, Laura D Wood.
      Neoadjuvant chemotherapy (NAC) is often the treatment of choice for borderline resectable and locally advanced invasive pancreatic ductal adenocarcinoma (PDAC); however, most cancers only partially respond to therapy. We hypothesized that the location of residual neoplastic cells in resected specimens following NAC could provide a clue as to the mechanisms of resistance. PDAC cells invade the stroma but can also invade back into and spread via the pancreatic ducts, which has been referred to as "cancerization of ducts" (COD). We compared the responsiveness to chemotherapy between PDAC cells in the stroma and PDAC cells in the duct. Pancreatic resections from a total of 174 PDAC patients (NAC, n = 97; immediate surgery, n = 77) were reviewed. On hematoxylin and eosin sections, COD was identified at the same prevalence in both groups (NAC: 50/97 cases, 52%; immediate surgery: 39/77 cases, 51%; p = 0.879, Fisher's exact test). However, using quantitative image analysis of CK19 immunohistochemistry, we found that the proportion of cancer cells that were intraductal was significantly different between the NAC and immediate surgery groups (median; 12.7% vs. 1.99%, p < 0.0001, Mann-Whitney U test). This proportion was highest in patients with marked therapy responses (36.2%) compared with patients with moderate or poor responses (7.21 & 7.91%). In summary, our data suggest that intraductal components in PDAC are less responsive to chemotherapy than the remainder of the tumor, which could have important implications for therapeutic resistance.
    DOI:  https://doi.org/10.1038/s41379-020-0572-6
  19. Biochem Biophys Res Commun. 2020 May 20. pii: S0006-291X(20)30893-7. [Epub ahead of print]
    Signal transducer and activator of transcription 5a (STAT5a) represses mitochondrial gene expression through direct binding to mitochondrial DNA.
    Fu-Yu Chueh, Ying-Ling Chang, Shin-Yu Wu, Chao-Lan Yu.
      Signal transducer and activator of transcription (STAT) proteins are latent cytoplasmic transcription factors essential for cytokine signaling. Our previous study showed that interleukin-3 (IL-3) induced STAT5 translocation to mitochondria and binding to mitochondrial DNA (mtDNA) in vitro. In this report, we further demonstrated in vivo binding of endogenous STAT5a to mtDNA transcriptional control region and reduced gene expression from all three mtDNA promoters after IL-3 stimulation. To specifically define the function of mitochondrial STAT5a, we generated mitochondrial-targeting wild-type and mutant STAT5a proteins. Compared with non-targeting STAT5a, mitochondrial-targeting wild-type STAT5a significantly reduced mitochondrial gene expression in transfected HEK293 cells. The level of attenuation was amplified in cells expressing constitutively active STAT5a, but abrogated in cells expressing DNA-binding-defective STAT5a. STAT5a-mediated repression of mtDNA expression also positively correlated with STAT5a binding to the E2 subunit of pyruvate dehydrogenase complex (PDC-E2), both a gate-keeping metabolic enzyme and a component of mtDNA nucleoid in mitochondrial matrix. Metabolic shift away from mitochondrial respiration is known in many cytokine-stimulated cells and cancer cells. STAT5a-mediated repression of mitochondrial gene expression and its interaction with PDC-E2 may provide important insights into its underlying mechanisms.
    Keywords:  Electron transport chain; Interleukin-3; Metabolism; Mitochondria; STAT5
    DOI:  https://doi.org/10.1016/j.bbrc.2020.04.152
  20. Nat Commun. 2020 May 26. 11(1): 2615
    Cryo-EM structures provide insight into how E. coli F1Fo ATP synthase accommodates symmetry mismatch.
    Meghna Sobti, James L Walshe, Di Wu, Robert Ishmukhametov, Yi C Zeng, Carol V Robinson, Richard M Berry, Alastair G Stewart.
      F1Fo ATP synthase functions as a biological rotary generator that makes a major contribution to cellular energy production. It comprises two molecular motors coupled together by a central and a peripheral stalk. Proton flow through the Fo motor generates rotation of the central stalk, inducing conformational changes in the F1 motor that catalyzes ATP production. Here we present nine cryo-EM structures of E. coli ATP synthase to 3.1-3.4 Å resolution, in four discrete rotational sub-states, which provide a comprehensive structural model for this widely studied bacterial molecular machine. We observe torsional flexing of the entire complex and a rotational sub-step of Fo associated with long-range conformational changes that indicates how this flexibility accommodates the mismatch between the 3- and 10-fold symmetries of the F1 and Fo motors. We also identify density likely corresponding to lipid molecules that may contribute to the rotor/stator interaction within the Fo motor.
    DOI:  https://doi.org/10.1038/s41467-020-16387-2
  21. Nat Rev Drug Discov. 2020 May 28.
    The quest to slow ageing through drug discovery.
    Linda Partridge, Matias Fuentealba, Brian K Kennedy.
      Although death is inevitable, individuals have long sought to alter the course of the ageing process. Indeed, ageing has proved to be modifiable; by intervening in biological systems, such as nutrient sensing, cellular senescence, the systemic environment and the gut microbiome, phenotypes of ageing can be slowed sufficiently to mitigate age-related functional decline. These interventions can also delay the onset of many disabling, chronic diseases, including cancer, cardiovascular disease and neurodegeneration, in animal models. Here, we examine the most promising interventions to slow ageing and group them into two tiers based on the robustness of the preclinical, and some clinical, results, in which the top tier includes rapamycin, senolytics, metformin, acarbose, spermidine, NAD+ enhancers and lithium. We then focus on the potential of the interventions and the feasibility of conducting clinical trials with these agents, with the overall aim of maintaining health for longer before the end of life.
    DOI:  https://doi.org/10.1038/s41573-020-0067-7
  22. Physiol Rev. 2020 May 28.
    DIVERSITY AND BIOLOGY OF CANCER-ASSOCIATED FIBROBLASTS.
    Giulia Biffi, David A Tuveson.
      Efforts to develop anti-cancer therapies have largely focused on targeting the epithelial compartment, despite the presence of non-neoplastic stromal components that substantially contribute to the progression of the tumor. Indeed, cancer cell survival, growth, migration and even dormancy are influenced by the surrounding tumor microenvironment (TME). Within the TME, cancer-associated fibroblasts (CAFs) have been shown to play several roles in the development of a tumor. They secrete growth factors, inflammatory ligands and extracellular matrix proteins that promote cancer cell proliferation, therapy resistance and immune exclusion. However, recent work indicates that CAFs may also restrain tumor progression in some circumstances. In this review, we summarize the body of work on CAFs, with a particular focus on the most recent discoveries about fibroblast heterogeneity, plasticity and functions. We also highlight the commonalities of fibroblasts present across different cancer types, and in normal and inflammatory states. Finally, we present the latest advances regarding therapeutic strategies targeting CAFs that are undergoing pre-clinical and clinical evaluation.
    Keywords:  Cancer; Fibroblasts; Heterogeneity; Plasticity
    DOI:  https://doi.org/10.1152/physrev.00048.2019
  23. Trends Cancer. 2020 Jun;pii: S2405-8033(20)30077-7. [Epub ahead of print]6(6): 454-461
    Perturbation-Driven Entropy as a Source of Cancer Cell Heterogeneity.
    Sebastian M B Nijman.
      Intratumor heterogeneity is a key hallmark of cancer that contributes to progression and therapeutic resistance. Phenotypic heterogeneity is in part caused by Darwinian selection of subclones that arise by random (epi)genetic aberrations. In addition, cancer cells are endowed with increased cellular plasticity compared with their normal counterparts, further adding to their heterogeneous behavior. However, the molecular mechanisms underpinning cancer cell plasticity are incompletely understood. Here, I outline the hypothesis that cancer-associated perturbations collectively disrupt normal gene regulatory networks (GRNs) by increasing their entropy. Importantly, in this model both somatic driver and passenger alterations contribute to 'perturbation-driven entropy', thereby increasing phenotypic heterogeneity and evolvability. This additional layer of heterogeneity may contribute to our understanding of cancer evolution and therapeutic resistance.
    Keywords:  cancer heterogeneity; entropy; gene regulatory networks; therapeutic resistance
    DOI:  https://doi.org/10.1016/j.trecan.2020.02.016
  24. Development. 2020 May 28. pii: dev175596. [Epub ahead of print]147(10):
    The extracellular matrix in development.
    David A Cruz Walma, Kenneth M Yamada.
      As the crucial non-cellular component of tissues, the extracellular matrix (ECM) provides both physical support and signaling regulation to cells. Some ECM molecules provide a fibrillar environment around cells, while others provide a sheet-like basement membrane scaffold beneath epithelial cells. In this Review, we focus on recent studies investigating the mechanical, biophysical and signaling cues provided to developing tissues by different types of ECM in a variety of developing organisms. In addition, we discuss how the ECM helps to regulate tissue morphology during embryonic development by governing key elements of cell shape, adhesion, migration and differentiation.
    Keywords:  Adhesion; Biophysical; Differentiation; Embryo; Extracellular matrix; Migration
    DOI:  https://doi.org/10.1242/dev.175596
  25. Hepatology. 2020 May 27.
    Lipid remodelling in hepatocyte proliferation and hepatocellular carcinoma.
    Zoe Hall, Davide Chiarugi, Evelina Charidemou, Jack Leslie, Emma Scott, Luca Pelligrinet, Michael Allison, Gabriele Mocciaro, Quentin M Anstee, Gerard I Evan, Matthew Hoare, Antonio Vidal-Puig, Fiona Oakley, Michele Vacca, Julian L Griffin.
       BACKGROUND & AIMS: Hepatocytes undergo profound metabolic rewiring when primed to proliferate during compensatory regeneration and in hepatocellular carcinoma (HCC). However, the metabolic control of these processes is not fully understood. In order to capture the metabolic signature of proliferating hepatocytes, we applied state-of-the-art systems biology approaches to models of liver regeneration, pharmacologically- and genetically-activated cell proliferation, and HCC.
    APPROACH & RESULTS: Integrating metabolomics, lipidomics and transcriptomics, we link changes in the lipidome of proliferating hepatocytes to altered metabolic pathways including lipogenesis, fatty acid desaturation, and generation of phosphatidylcholine (PC). We confirm this altered lipid signature in human HCC and show a positive correlation of monounsaturated-PC with hallmarks of cell proliferation and hepatic carcinogenesis.
    CONCLUSION: Overall, we demonstrate that specific lipid metabolic pathways are coherently altered when hepatocytes switch to proliferation. These represent a source of targets for the development of new therapeutic strategies and prognostic biomarkers of HCC.
    Keywords:  HCC; cancer metabolism; liver regeneration; mass spectrometry imaging; phosphatidylcholine
    DOI:  https://doi.org/10.1002/hep.31391
  26. Trends Cancer. 2020 May 26. pii: S2405-8033(20)30155-2. [Epub ahead of print]
    Tunneling Nanotubes: The Fuel of Tumor Progression?
    Giulia Pinto, Christel Brou, Chiara Zurzolo.
      Tunneling nanotubes (TNTs) are thin membrane tubes connecting remote cells and allowing the transfer of cellular content. TNTs have been reported in several cancer in vitro, ex vivo, and in vivo models. Cancer cells exploit TNT-like connections to exchange material between themselves or with the tumoral microenvironment. Cells acquire new abilities (e.g., enhanced metabolic plasticity, migratory phenotypes, angiogenic ability, and therapy resistance) via these exchanges, contributing to cancer aggressiveness. Here, we review the morphological and functional features of TNT-like structures and their impact on cancer progression and resistance to therapies. Finally, we discuss the case of glioblastoma (GBM), in which a functional and resistant network between cancer cells in an in vivo model has been described for the first time.
    Keywords:  cancer; cell-to-cell communication; glioblastoma; tunneling nanotubes
    DOI:  https://doi.org/10.1016/j.trecan.2020.04.012
  27. Cell. 2020 May 28. pii: S0092-8674(20)30508-0. [Epub ahead of print]181(5): 1112-1130.e16
    Molecular Choreography of Acute Exercise.
    Kévin Contrepois, Si Wu, Kegan J Moneghetti, Daniel Hornburg, Sara Ahadi, Ming-Shian Tsai, Ahmed A Metwally, Eric Wei, Brittany Lee-McMullen, Jeniffer V Quijada, Songjie Chen, Jeffrey W Christle, Mathew Ellenberger, Brunilda Balliu, Shalina Taylor, Matthew G Durrant, David A Knowles, Hani Choudhry, Melanie Ashland, Amir Bahmani, Brooke Enslen, Myriam Amsallem, Yukari Kobayashi, Monika Avina, Dalia Perelman, Sophia Miryam Schüssler-Fiorenza Rose, Wenyu Zhou, Euan A Ashley, Stephen B Montgomery, Hassan Chaib, Francois Haddad, Michael P Snyder.
      Acute physical activity leads to several changes in metabolic, cardiovascular, and immune pathways. Although studies have examined selected changes in these pathways, the system-wide molecular response to an acute bout of exercise has not been fully characterized. We performed longitudinal multi-omic profiling of plasma and peripheral blood mononuclear cells including metabolome, lipidome, immunome, proteome, and transcriptome from 36 well-characterized volunteers, before and after a controlled bout of symptom-limited exercise. Time-series analysis revealed thousands of molecular changes and an orchestrated choreography of biological processes involving energy metabolism, oxidative stress, inflammation, tissue repair, and growth factor response, as well as regulatory pathways. Most of these processes were dampened and some were reversed in insulin-resistant participants. Finally, we discovered biological pathways involved in cardiopulmonary exercise response and developed prediction models revealing potential resting blood-based biomarkers of peak oxygen consumption.
    Keywords:  cardiopulmonary exercise testing; fitness; insulin resistance; multi-omics; outlier analysis; peak VO(2); physical activity; predictive analytics; systems biology; time-series analysis
    DOI:  https://doi.org/10.1016/j.cell.2020.04.043
  28. Sci Signal. 2020 May 26. pii: eaay8203. [Epub ahead of print]13(633):
    Myeloma cells shift osteoblastogenesis to adipogenesis by inhibiting the ubiquitin ligase MURF1 in mesenchymal stem cells.
    Zhiqiang Liu, Huan Liu, Jin He, Pei Lin, Qiang Tong, Jing Yang.
      The suppression of bone formation is a hallmark of multiple myeloma. Myeloma cells inhibit osteoblastogenesis from mesenchymal stem cells (MSCs), which can also differentiate into adipocytes. We investigated myeloma-MSC interactions and the effects of such interactions on the differentiation of MSCs into adipocytes or osteoblasts using single-cell RNA sequencing, in vitro coculture, and subcutaneous injection of MSCs and myeloma cells into mice. Our results revealed that the α4 integrin subunit on myeloma cells stimulated vascular cell adhesion molecule-1 (VCAM1) on MSCs, leading to the activation of protein kinase C β1 (PKCβ1) signaling and repression of the muscle ring-finger protein-1 (MURF1)-mediated ubiquitylation of peroxisome proliferator-activated receptor γ2 (PPARγ2). Stabilized PPARγ2 proteins enhanced adipogenesis and consequently reduced osteoblastogenesis from MSCs, thus suppressing bone formation in vitro and in vivo. These findings reveal that suppressed bone formation is a direct consequence of myeloma-MSC contact that promotes the differentiation of MSCs into adipocytes at the expense of osteoblasts. Thus, this study provides a potential strategy for treating bone resorption in patients with myeloma by counteracting tumor-MSC interactions.
    DOI:  https://doi.org/10.1126/scisignal.aay8203
  29. Nature. 2020 May;581(7809): 382-383
    Take lessons from cancer evolution to the clinic.
    Charles Swanton.
      
    Keywords:  Cancer; Genetics; Health care; Medical research
    DOI:  https://doi.org/10.1038/d41586-020-01347-z
  30. Cancer Cell. 2020 May 13. pii: S1535-6108(20)30215-4. [Epub ahead of print]
    MAX Functions as a Tumor Suppressor and Rewires Metabolism in Small Cell Lung Cancer.
    Arnaud Augert, Haritha Mathsyaraja, Ali H Ibrahim, Brian Freie, Michael J Geuenich, Pei-Feng Cheng, Sydney P Alibeckoff, Nan Wu, Joseph B Hiatt, Ryan Basom, Adi Gazdar, Lucas B Sullivan, Robert N Eisenman, David MacPherson.
      Small cell lung cancer (SCLC) is a highly aggressive and lethal neoplasm. To identify candidate tumor suppressors we applied CRISPR/Cas9 gene inactivation screens to a cellular model of early-stage SCLC. Among the top hits was MAX, the obligate heterodimerization partner for MYC family proteins that is mutated in human SCLC. Max deletion increases growth and transformation in cells and dramatically accelerates SCLC progression in an Rb1/Trp53-deleted mouse model. In contrast, deletion of Max abrogates tumorigenesis in MYCL-overexpressing SCLC. Max deletion in SCLC resulted in derepression of metabolic genes involved in serine and one-carbon metabolism. By increasing serine biosynthesis, Max-deleted cells exhibit resistance to serine depletion. Thus, Max loss results in metabolic rewiring and context-specific tumor suppression.
    Keywords:  CRISPR-Cas9 genetic screens; MAX; MYC; SCLC; Transcriptional regulation; cancer; mouse model; serine and one-carbon metabolism; small cell lung cancer; tumor suppressor genes
    DOI:  https://doi.org/10.1016/j.ccell.2020.04.016
  31. J Exp Med. 2020 Aug 03. pii: e20190673. [Epub ahead of print]217(8):
    Type 1 conventional dendritic cells are systemically dysregulated early in pancreatic carcinogenesis.
    Jeffrey H Lin, Austin P Huffman, Max M Wattenberg, David M Walter, Erica L Carpenter, David M Feldser, Gregory L Beatty, Emma E Furth, Robert H Vonderheide.
      Type 1 conventional dendritic cells (cDC1s) are typically thought to be dysregulated secondarily to invasive cancer. Here, we report that cDC1 dysfunction instead develops in the earliest stages of preinvasive pancreatic intraepithelial neoplasia (PanIN) in the KrasLSL-G12D/+ Trp53LSL-R172H/+ Pdx1-Cre-driven (KPC) mouse model of pancreatic cancer. cDC1 dysfunction is systemic and progressive, driven by increased apoptosis, and results in suboptimal up-regulation of T cell-polarizing cytokines during cDC1 maturation. The underlying mechanism is linked to elevated IL-6 concomitant with neoplasia. Neutralization of IL-6 in vivo ameliorates cDC1 apoptosis, rescuing cDC1 abundance in tumor-bearing mice. CD8+ T cell response to vaccination is impaired as a result of cDC1 dysregulation. Yet, combination therapy with CD40 agonist and Flt3 ligand restores cDC1 abundance to normal levels, decreases cDC1 apoptosis, and repairs cDC1 maturation to drive superior control of tumor outgrowth. Our study therefore reveals the unexpectedly early and systemic onset of cDC1 dysregulation during pancreatic carcinogenesis and suggests therapeutically tractable strategies toward cDC1 repair.
    DOI:  https://doi.org/10.1084/jem.20190673
  32. J Cell Biol. 2020 Jul 06. pii: e201910063. [Epub ahead of print]219(7):
    TORC1 inactivation stimulates autophagy of nucleoporin and nuclear pore complexes.
    Yui Tomioka, Tetsuya Kotani, Hiromi Kirisako, Yu Oikawa, Yayoi Kimura, Hisashi Hirano, Yoshinori Ohsumi, Hitoshi Nakatogawa.
      The mechanisms underlying turnover of the nuclear pore complex (NPC) and the component nucleoporins (Nups) are still poorly understood. In this study, we found that the budding yeast Saccharomyces cerevisiae triggers NPC degradation by autophagy upon the inactivation of Tor kinase complex 1. This degradation largely depends on the selective autophagy-specific factor Atg11 and the autophagy receptor-binding ability of Atg8, suggesting that the NPC is degraded via receptor-dependent selective autophagy. Immunoelectron microscopy revealed that NPCs embedded in nuclear envelope-derived double-membrane vesicles are sequestered within autophagosomes. At least two pathways are involved in NPC degradation: Atg39-dependent nucleophagy (selective autophagy of the nucleus) and a pathway involving an unknown receptor. In addition, we found the interaction between Nup159 and Atg8 via the Atg8-family interacting motif is important for degradation of this nucleoporin not assembled into the NPC. Thus, this study provides the first evidence for autophagic degradation of the NPC and Nups, which we term "NPC-phagy" and "nucleoporinophagy."
    DOI:  https://doi.org/10.1083/jcb.201910063
  33. Nat Rev Endocrinol. 2020 May 27.
    Unravelling novel weight loss mechanisms.
    Alan Morris.
      
    DOI:  https://doi.org/10.1038/s41574-020-0374-4
  34. Mol Cell. 2020 May 17. pii: S1097-2765(20)30277-X. [Epub ahead of print]
    Biomarker-Guided Development of DNA Repair Inhibitors.
    James M Cleary, Andrew J Aguirre, Geoffrey I Shapiro, Alan D D'Andrea.
      Anti-cancer drugs targeting the DNA damage response (DDR) exploit genetic or functional defects in this pathway through synthetic lethal mechanisms. For example, defects in homologous recombination (HR) repair arise in cancer cells through inherited or acquired mutations in BRCA1, BRCA2, or other genes in the Fanconi anemia/BRCA pathway, and these tumors have been shown to be particularly sensitive to inhibitors of the base excision repair (BER) protein poly (ADP-ribose) polymerase (PARP). Recent work has identified additional genomic and functional assays of DNA repair that provide new predictive and pharmacodynamic biomarkers for these targeted therapies. Here, we examine the development of selective agents targeting DNA repair, including PARP inhibitors; inhibitors of the DNA damage kinases ataxia-telangiectasia and Rad3 related (ATR), CHK1, WEE1, and ataxia-telangiectasia mutated (ATM); and inhibitors of classical non-homologous end joining (cNHEJ) and alternative end joining (Alt EJ). We also review the biomarkers that guide the use of these agents and current clinical trials with these therapies.
    Keywords:  DNA repair; PARP inhibitor; cell-cycle kinases; polymerase theta
    DOI:  https://doi.org/10.1016/j.molcel.2020.04.035
  35. Trends Cancer. 2020 Jun;pii: S2405-8033(20)30081-9. [Epub ahead of print]6(6): 489-505
    Tumour Cell Secretome in Chemoresistance and Tumour Recurrence.
    Emma C Madden, Adrienne M Gorman, Susan E Logue, Afshin Samali.
      Chemoresistance is a major factor driving tumour relapse and the high rates of cancer-related deaths. Understanding how cancer cells overcome chemotherapy-induced cell death is critical in promoting patient survival. One emerging mechanism of chemoresistance is the tumour cell secretome (TCS), an array of protumorigenic factors released by tumour cells. Chemotherapy exposure can also alter the composition of the TCS, known as therapy-induced TCS, and can promote tumour relapse and the formation of an immunosuppressive tumour microenvironment (TME). Here, we outline how the TCS can protect cancer cells from chemotherapy-induced cell death. We also highlight recent evidence describing how therapy-induced TCS can impact cancer stem cell (CSC) expansion and tumour-associated immune cells to enable tumour regrowth and antitumour immunity.
    Keywords:  cancer stem cells (CSCs); chemoresistance; immune escape, tumour cell secretome (TCS); tumour microenvironment (TME); tumour relapse
    DOI:  https://doi.org/10.1016/j.trecan.2020.02.020
  36. J Physiol. 2020 May 29.
    Cerebrovascular reactivity: a new frontier for measuring cognitive health in models of accelerated aging?
    David A Hutton, Alyssa N Cavalier, Zachary S Clayton.
      
    Keywords:  accelerated aging; aging; anthracyclines; cerebrovascular reactivity; cognitive function; vascular aging
    DOI:  https://doi.org/10.1113/JP279949
  37. Science. 2020 May 27. pii: eabc6197. [Epub ahead of print]
    Reducing transmission of SARS-CoV-2.
    Kimberly A Prather, Chia C Wang, Robert T Schooley.
      Masks and testing are necessary to combat asymptomatic spread in aerosols and droplets.
    DOI:  https://doi.org/10.1126/science.abc6197
  38. Sci Signal. 2020 May 26. pii: eaba3176. [Epub ahead of print]13(633):
    IGF-1 receptor activity in the Golgi of migratory cancer cells depends on adhesion-dependent phosphorylation of Tyr1250 and Tyr1251.
    Leonie Rieger, Sandra O'Shea, Grant Godsmark, Joanna Stanicka, Geraldine Kelly, Rosemary O'Connor.
      Although insulin-like growth factor 1 (IGF-1) signaling promotes tumor growth and cancer progression, therapies that target the IGF-1 receptor (IGF-1R) have shown poor clinical efficacy. To address IGF-1R activity in cancer cells and how it differs from that of the closely related insulin receptor (IR), we focused on two tyrosines in the IGF-1R C-terminal tail that are not present in the IR and are essential for IGF-1-mediated cancer cell survival, migration, and tumorigenic growth. We found that Tyr1250 and Tyr1251 (Tyr1250/1251) were autophosphorylated in a cell adhesion-dependent manner. To investigate the consequences of this phosphorylation, we generated phosphomimetic Y1250E/Y1251E (EE) and nonphosphorylatable Y1250F/Y1251F (FF) mutant forms of IGF-1R. Although fully competent in kinase activity and signaling, the EE mutant was more rapidly internalized and degraded than either the wild-type or FF receptor. IGF-1 promoted the accumulation of wild-type and EE IGF-1R within the Golgi apparatus, whereas the FF mutant remained at the plasma membrane. Golgi-associated IGF-1R signaling was a feature of migratory cancer cells, and Golgi disruption impaired IGF-1-induced signaling and cell migration. Upon the formation of new cell adhesions, IGF-1R transiently relocalized to the plasma membrane from the Golgi. Thus, phosphorylation at Tyr1250/1251 promoted IGF-1R translocation to and signaling from the Golgi to support an aggressive cancer phenotype. This process distinguishes IGF-1R from IR signaling and could contribute to the poor clinical efficacy of antibodies that target IGF-1R on the cell surface.
    DOI:  https://doi.org/10.1126/scisignal.aba3176
  39. Elife. 2020 May 26. pii: e53074. [Epub ahead of print]9
    Limitation of adipose tissue by the number of embryonic progenitor cells.
    Kristina Hedbacker, Yi-Hsueh Lu, Olof Dallner, Zhiying Li, Gulya Fayzikhodjaeva, Kıvanç Birsoy, Chiayun Han, Chingwen Yang, Jeffrey M Friedman.
      Adipogenesis in adulthood replaces fat cells that turn over and can contribute to the development of obesity. However, the proliferative potential of adipocyte progenitors in vivo is unknown (Faust et al., 1976; Faust et al., 1977; Hirsch and Han, 1969; Johnson and Hirsch, 1972). We addressed this by injecting labeled wild-type embryonic stem cells into blastocysts derived from lipodystrophic A-ZIP transgenic mice, which have a genetic block in adipogenesis. In the resulting chimeric animals, wild-type ES cells are the only source of mature adipocytes. We found that when chimeric animals were fed a high-fat-diet, animals with low levels of chimerism showed a significantly lower adipose tissue mass than animals with high levels of chimerism. The difference in adipose tissue mass was attributed to variability in the amount of subcutaneous adipose tissue as the amount of visceral fat was independent of the level of chimerism. Our findings thus suggest that proliferative potential of adipocyte precursors is limited and can restrain the development of obesity.
    Keywords:  adipose tissue; cell biology; leptin; lipodystrophy; metabolic syndrome; metabolism; mouse; obesity
    DOI:  https://doi.org/10.7554/eLife.53074
  40. Nat Commun. 2020 May 29. 11(1): 2663
    Human ESCRT-III polymers assemble on positively curved membranes and induce helical membrane tube formation.
    Aurélie Bertin, Nicola de Franceschi, Eugenio de la Mora, Sourav Maiti, Maryam Alqabandi, Nolwen Miguet, Aurélie di Cicco, Wouter H Roos, Stéphanie Mangenot, Winfried Weissenhorn, Patricia Bassereau.
      Endosomal sorting complexes for transport-III (ESCRT-III) assemble in vivo onto membranes with negative Gaussian curvature. How membrane shape influences ESCRT-III polymerization and how ESCRT-III shapes membranes is yet unclear. Human core ESCRT-III proteins, CHMP4B, CHMP2A, CHMP2B and CHMP3 are used to address this issue in vitro by combining membrane nanotube pulling experiments, cryo-electron tomography and AFM. We show that CHMP4B filaments preferentially bind to flat membranes or to tubes with positive mean curvature. Both CHMP2B and CHMP2A/CHMP3 assemble on positively curved membrane tubes. Combinations of CHMP4B/CHMP2B and CHMP4B/CHMP2A/CHMP3 are recruited to the neck of pulled membrane tubes and reshape vesicles into helical "corkscrew-like" membrane tubes. Sub-tomogram averaging reveals that the ESCRT-III filaments assemble parallel and locally perpendicular to the tube axis, highlighting the mechanical stresses imposed by ESCRT-III. Our results underline the versatile membrane remodeling activity of ESCRT-III that may be a general feature required for cellular membrane remodeling processes.
    DOI:  https://doi.org/10.1038/s41467-020-16368-5
  41. Cells. 2020 May 23. pii: E1302. [Epub ahead of print]9(5):
    Protein Phase Separation during Stress Adaptation and Cellular Memory.
    Yasmin Lau, Henry Patrick Oamen, Fabrice Caudron.
      Cells need to organise and regulate their biochemical processes both in space and time in order to adapt to their surrounding environment. Spatial organisation of cellular components is facilitated by a complex network of membrane bound organelles. Both the membrane composition and the intra-organellar content of these organelles can be specifically and temporally controlled by imposing gates, much like bouncers controlling entry into night-clubs. In addition, a new level of compartmentalisation has recently emerged as a fundamental principle of cellular organisation, the formation of membrane-less organelles. Many of these structures are dynamic, rapidly condensing or dissolving and are therefore ideally suited to be involved in emergency cellular adaptation to stresses. Remarkably, the same proteins have also the propensity to adopt self-perpetuating assemblies which properties fit the needs to encode cellular memory. Here, we review some of the principles of phase separation and the function of membrane-less organelles focusing particularly on their roles during stress response and cellular memory.
    Keywords:  cellular memory; phase separation; prions; stress
    DOI:  https://doi.org/10.3390/cells9051302
  42. Aging Cell. 2020 May 25. e13151
    TORC1 signaling regulates cytoplasmic pH through Sir2 in yeast.
    Mayur Nimbadas Devare, Yeong Hyeock Kim, Joohye Jung, Woo Kyu Kang, Ki-Sun Kwon, Jeong-Yoon Kim.
      Glucose controls the phosphorylation of silent information regulator 2 (Sir2), a NAD+ -dependent protein deacetylase, which regulates the expression of the ATP-dependent proton pump Pma1 and replicative lifespan (RLS) in yeast. TORC1 signaling, which is a central regulator of cell growth and lifespan, is regulated by glucose as well as nitrogen sources. In this study, we demonstrate that TORC1 signaling controls Sir2 phosphorylation through casein kinase 2 (CK2) to regulate PMA1 expression and cytoplasmic pH (pHc) in yeast. Inhibition of TORC1 signaling by either TOR1 deletion or rapamycin treatment decreased PMA1 expression, pHc, and vacuolar pH, whereas activation of TORC1 signaling by expressing constitutively active GTR1 (GTR1Q65L) resulted in the opposite phenotypes. Deletion of SIR2 or expression of a phospho-mutant form of SIR2 increased PMA1 expression, pHc, and vacuolar pH in the tor1Δ mutant, suggesting a functional interaction between Sir2 and TORC1 signaling. Furthermore, deletion of TOR1 or KNS1 encoding a LAMMER kinase decreased the phosphorylation level of Sir2, suggesting that TORC1 signaling controls Sir2 phosphorylation. It was also found that Sit4, a protein phosphatase 2A (PP2A)-like phosphatase, and Kns1 are required for TORC1 signaling to regulate PMA1 expression and that TORC1 signaling and the cyclic AMP (cAMP)/protein kinase A (PKA) pathway converge on CK2 to regulate PMA1 expression through Sir2. Taken together, these findings suggest that TORC1 signaling regulates PMA1 expression and pHc through the CK2-Sir2 axis, which is also controlled by cAMP/PKA signaling in yeast.
    Keywords:   Saccharomyces cerevisiae ; Pma1; Sir2; TORC1; aging; cytoplasmic pH
    DOI:  https://doi.org/10.1111/acel.13151
  43. Trends Biochem Sci. 2020 May 21. pii: S0968-0004(20)30118-3. [Epub ahead of print]
    Coupling of Ribosome Synthesis and Translational Capacity with Cell Growth.
    Xiongfeng Dai, Manlu Zhu.
      Ribosome and protein synthesis lie at the core of cell growth and are major consumers of the cellular budget. Here we review recent progress in the coupling of ribosome synthesis and translational capacity with cell growth in bacteria. We elaborate on the different strategies of bacteria to modulate the protein synthesis rate at fast and slow growth rates. In particular, bacterial cells maintain translational potential at very slow growth as a strategy to keep fitness in fluctuating environments. We further discuss the important role of ribosome synthesis in rapidly proliferating eukaryotic cells such as yeast cells and cancer cells. The tight relation between ribosome and cell growth provides a broad research avenue for researchers from various disciplines.
    Keywords:  bacterial growth; cancer cell growth; nutrient availability; protein synthesis; yeast growth
    DOI:  https://doi.org/10.1016/j.tibs.2020.04.010
  44. J Cell Sci. 2020 May 28. pii: jcs.246330. [Epub ahead of print]
    Investigating cell cycle-dependent gene expression in the context of nuclear architecture at a single allele resolution.
    Shivnarayan Dhuppar, Aprotim Mazumder.
      Nuclear architecture is the organization of the genome within a cell nucleus with respect to different nuclear landmarks such as nuclear lamina, matrix or nucleoli. Lately it has emerged as a major regulator of gene expression in mammalian cells. The studies connecting nuclear architecture with gene expression are largely population-averaged and do not report on the heterogeneity in genome organization or in gene expression within a population. In this report we present a method for combining 3D DNA Fluorescence in situ Hybridization (FISH) with single molecule RNA FISH (smFISH) and immunofluorescence to study nuclear architecture-dependent gene regulation on a cell-by-cell basis. We further combine it with an imaging-based cell cycle staging to correlate nuclear architecture with gene expression across the cell cycle. We present this in the context of Cyclin A2 (CCNA2) gene for its known cell cycle-dependent expression. We show that, across the cell cycle, the expression of a CCNA2 gene copy is stochastic and depends neither on its sub-nuclear position-which usually lies close to nuclear lamina-nor on the expression from the other copies.
    Keywords:  3D nuclear architecture; Cell cycle; Central dogma; Cyclin A2; DNA FISH; Immunofluorescence; Nuclear lamina; SmFISH
    DOI:  https://doi.org/10.1242/jcs.246330
  45. Mol Neurobiol. 2020 May 25.
    The Mitochondria-Associated ER Membranes Are Novel Subcellular Locations Enriched for Inflammatory-Responsive MicroRNAs.
    Wang-Xia Wang, Paresh Prajapati, Peter T Nelson, Joe E Springer.
      The mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are specific ER domains that contact the mitochondria and function to facilitate communication between ER and mitochondria. Disruption of contact between the mitochondria and ER is associated with a variety of pathophysiological conditions including neurodegenerative diseases. Considering the many cellular functions of MAMs, we hypothesized that MAMs play an important role in regulating microRNA (miRNA) activity linked to its unique location between mitochondria and ER. Here we present new findings from human and rat brains indicating that the MAMs are subcellular sites enriched for specific miRNAs. We employed subcellular fractionation and TaqMan® RT-qPCR miRNA analysis to quantify miRNA levels in subcellular fractions isolated from male rat brains and six human brain samples. We found that MAMs contain a substantial number of miRNAs and the profile differs significantly from that of cytosolic, mitochondria, or ER. Interestingly, MAMs are particularly enriched in inflammatory-responsive miRNAs, including miR-146a, miR-142-3p, and miR-142-5p in both human and rat brains; miR-223 MAM enrichment was observed only in human brain samples. Further, mitochondrial uncoupling or traumatic brain injury in male rats resulted in the alteration of inflammatory miRNA enrichment in the isolated subcellular fractions. These observations demonstrate that miRNAs are distributed differentially in organelles and may re-distribute between organelles and the cytosol in response to cellular stress and metabolic demands.
    Keywords:  Mitochondria-associated ER membrane; Neurodegeneration; Subcellular; Traumatic brain injury; miR-146a; microRNA
    DOI:  https://doi.org/10.1007/s12035-020-01937-y
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