bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2021–05–16
fifty papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Autophagy is critical for cysteine metabolism in pancreatic cancer through regulation of SLC7A11.
  2. Sulfopin is a covalent inhibitor of Pin1 that blocks Myc-driven tumors in vivo.
  3. NRF2 activates macropinocytosis upon autophagy inhibition.
  4. An aged immune system drives senescence and ageing of solid organs.
  5. Translational Control of Immune Evasion in Cancer.
  6. Cancer-associated fibroblasts in pancreatic ductal adenocarcinoma determine response to SLC7A11 inhibition.
  7. PI5P4Ks drive metabolic homeostasis through peroxisome-mitochondria interplay.
  8. A TORC1-histone axis regulates chromatin organisation and non-canonical induction of autophagy to ameliorate ageing.
  9. Single-PanIN-seq unveils that ARID1A deficiency promotes pancreatic tumorigenesis by attenuating KRAS-induced senescence.
  10. Peripheral-specific Y1 receptor antagonism increases thermogenesis and protects against diet-induced obesity.
  11. The liver metastatic niche: modelling the extracellular matrix in metastasis.
  12. Detecting and Rescuing Stalled Ribosomes.
  13. CREG1 promotes lysosomal biogenesis and function.
  14. Chromatin accessibility governs the differential response of cancer and T cells to arginine starvation.
  15. Cell-specific transcriptional control of mitochondrial metabolism by TIF1γ drives erythropoiesis.
  16. A subcellular map of the human kinome.
  17. PRKA/PKA signals and autophagy: space matters.
  18. Cancer microenvironment and genomics: evolution in process.
  19. Cross-tissue organization of the fibroblast lineage.
  20. Glycolytic ATP fuels phosphoinositide 3-kinase signaling to support effector T helper 17 cell responses.
  21. Mitochondrial matrix proteases - quality control and beyond.
  22. Molecular Profiling Practices in Pancreatic Adenocarcinoma: Academic vs Community Physicians.
  23. Slow-Cycling (Dormant) Cancer Cells in Therapy Resistance, Cancer Relapse and Metastasis.
  24. CD8+ T cell metabolism in infection and cancer.
  25. The principles of directed cell migration.
  26. The Warburg Effect: Historical Dogma Versus Current Rationale.
  27. The inflammatory speech of fibroblasts.
  28. Non-canonical NRF2 activation promotes a pro-diabetic shift in hepatic glucose metabolism.
  29. A prometastatic splicing program regulated by SNRPA1 interactions with structured RNA elements.
  30. ArfGAP1 inhibits mTORC1 lysosomal localization and activation.
  31. Mitochondria: A critical hub for hepatic stellate cells activation during chronic liver diseases: Mitochondria in hepatic stellate cells.
  32. Cancer cachexia: molecular mechanism and pharmacological management.
  33. High-throughput full-length single-cell RNA-seq automation.
  34. Neutrophil elastase selectively kills cancer cells and attenuates tumorigenesis.
  35. Cork-in-bottle mechanism of inhibitor binding to mammalian complex I.
  36. A novel classification of portal venous tumor invasion to predict residual tumor status after surgery in patients with pancreatic neuroendocrine neoplasms.
  37. Decoupling epithelial-mesenchymal transitions from stromal profiles by integrative expression analysis.
  38. Phosphoregulation of the autophagy machinery by kinases and phosphatases.
  39. Angelika Amon (1967-2020).
  40. Multi-omic profiling of lung and liver tumor microenvironments of metastatic pancreatic cancer reveals site-specific immune regulatory pathways.
  41. Conversion surgery in patients with pancreatic cancer and peritoneal metastasis.
  42. Identification, Validation, and Utilization of Immune Cells in Pancreatic Ductal Adenocarcinoma Based on Marker Genes.
  43. Hallmarks of T cell aging.
  44. Limited inhibition of multiple nodes in a driver network blocks metastasis.
  45. Integrative modeling identifies genetic ancestry-associated molecular correlates in human cancer.
  46. Selective and noncovalent targeting of RAS mutants for inhibition and degradation.
  47. Interplay Between Glucose Metabolism and Chromatin Modifications in Cancer.
  48. Dissecting lipid droplet biology with coherent Raman scattering microscopy.
  49. Noninvasive visualization of electrical conductivity in tissues at the micrometer scale.
  50. Imaging developmental cell cycles.
  1. Autophagy. 2021 May 14. 1-2
    Autophagy is critical for cysteine metabolism in pancreatic cancer through regulation of SLC7A11.
    Subhadip Mukhopadhyay, Alec C Kimmelman.
      Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer. The elevated macroautophagy/autophagy in these tumors supports growth, promotes immune evasion, and increases therapeutic resistance. Therefore, targeting autophagy is a therapeutic strategy that is being pursued to treat PDAC patients. Whereas autophagy inhibition impairs mitochondrial metabolism in PDAC, the specific metabolite(s) that becomes limiting when autophagy is inhibited has not been identified. We report that loss of autophagy specifically results in intracellular cysteine depletion under nutrient-replete conditions. Mechanistically, we show that PDAC cells utilize the autophagy machinery to regulate the activity and localization of the cystine transporter SLC7A11 at the plasma membrane. Upon inhibition of autophagy, SLC7A11 is localized to lysosomes in an MTORC2-dependent manner. Our findings reveal a novel connection between autophagy and cysteine metabolism in pancreatic cancer.
    Keywords:  Autophagy; SLC7A11; cysteine; lysosome; metabolism; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.1080/15548627.2021.1922984
  2. Nat Chem Biol. 2021 May 10.
    Sulfopin is a covalent inhibitor of Pin1 that blocks Myc-driven tumors in vivo.
    Christian Dubiella, Benika J Pinch, Kazuhiro Koikawa, Daniel Zaidman, Evon Poon, Theresa D Manz, Behnam Nabet, Shuning He, Efrat Resnick, Adi Rogel, Ellen M Langer, Colin J Daniel, Hyuk-Soo Seo, Ying Chen, Guillaume Adelmant, Shabnam Sharifzadeh, Scott B Ficarro, Yann Jamin, Barbara Martins da Costa, Mark W Zimmerman, Xiaolan Lian, Shin Kibe, Shingo Kozono, Zainab M Doctor, Christopher M Browne, Annan Yang, Liat Stoler-Barak, Richa B Shah, Nicholas E Vangos, Ezekiel A Geffken, Roni Oren, Eriko Koide, Samuel Sidi, Ziv Shulman, Chu Wang, Jarrod A Marto, Sirano Dhe-Paganon, Thomas Look, Xiao Zhen Zhou, Kun Ping Lu, Rosalie C Sears, Louis Chesler, Nathanael S Gray, Nir London.
      The peptidyl-prolyl isomerase, Pin1, is exploited in cancer to activate oncogenes and inactivate tumor suppressors. However, despite considerable efforts, Pin1 has remained an elusive drug target. Here, we screened an electrophilic fragment library to identify covalent inhibitors targeting Pin1's active site Cys113, leading to the development of Sulfopin, a nanomolar Pin1 inhibitor. Sulfopin is highly selective, as validated by two independent chemoproteomics methods, achieves potent cellular and in vivo target engagement and phenocopies Pin1 genetic knockout. Pin1 inhibition had only a modest effect on cancer cell line viability. Nevertheless, Sulfopin induced downregulation of c-Myc target genes, reduced tumor progression and conferred survival benefit in murine and zebrafish models of MYCN-driven neuroblastoma, and in a murine model of pancreatic cancer. Our results demonstrate that Sulfopin is a chemical probe suitable for assessment of Pin1-dependent pharmacology in cells and in vivo, and that Pin1 warrants further investigation as a potential cancer drug target.
    DOI:  https://doi.org/10.1038/s41589-021-00786-7
  3. Cancer Cell. 2021 May 10. pii: S1535-6108(21)00169-0. [Epub ahead of print]39(5): 596-598
    NRF2 activates macropinocytosis upon autophagy inhibition.
    Gourish Mondal, Jayanta Debnath.
      Su et al. demonstrate that upon inhibiting autophagy, an intracellular nutrient recycling pathway, pancreatic ductal adenocarcinoma cells upregulate NRF2-mediated transcription of macropinocytosis pathway components, thereby triggering an alternate route for tumors to scavenge nutrients from extracellular sources. Accordingly, the combined inhibition of autophagy and macropinocytosis may improve cancer treatment.
    DOI:  https://doi.org/10.1016/j.ccell.2021.03.011
  4. Nature. 2021 May 12.
    An aged immune system drives senescence and ageing of solid organs.
    Matthew J Yousefzadeh, Rafael R Flores, Yi Zhu, Zoe C Schmiechen, Robert W Brooks, Christy E Trussoni, Yuxiang Cui, Luise Angelini, Kyoo-A Lee, Sara J McGowan, Adam L Burrack, Dong Wang, Qing Dong, Aiping Lu, Tokio Sano, Ryan D O'Kelly, Collin A McGuckian, Jonathan I Kato, Michael P Bank, Erin A Wade, Smitha P S Pillai, Jenna Klug, Warren C Ladiges, Christin E Burd, Sara E Lewis, Nicholas F LaRusso, Nam V Vo, Yinsheng Wang, Eric E Kelley, Johnny Huard, Ingunn M Stromnes, Paul D Robbins, Laura J Niedernhofer.
      Ageing of the immune system, or immunosenescence, contributes to the morbidity and mortality of the elderly1,2. To define the contribution of immune system ageing to organism ageing, here we selectively deleted Ercc1, which encodes a crucial DNA repair protein3,4, in mouse haematopoietic cells to increase the burden of endogenous DNA damage and thereby senescence5-7 in the immune system only. We show that Vav-iCre+/-;Ercc1-/fl mice were healthy into adulthood, then displayed premature onset of immunosenescence characterized by attrition and senescence of specific immune cell populations and impaired immune function, similar to changes that occur during ageing in wild-type mice8-10. Notably, non-lymphoid organs also showed increased senescence and damage, which suggests that senescent, aged immune cells can promote systemic ageing. The transplantation of splenocytes from Vav-iCre+/-;Ercc1-/fl or aged wild-type mice into young mice induced senescence in trans, whereas the transplantation of young immune cells attenuated senescence. The treatment of Vav-iCre+/-;Ercc1-/fl mice with rapamycin reduced markers of senescence in immune cells and improved immune function11,12. These data demonstrate that an aged, senescent immune system has a causal role in driving systemic ageing and therefore represents a key therapeutic target to extend healthy ageing.
    DOI:  https://doi.org/10.1038/s41586-021-03547-7
  5. Trends Cancer. 2021 May 07. pii: S2405-8033(21)00082-0. [Epub ahead of print]
    Translational Control of Immune Evasion in Cancer.
    Shruthy Suresh, Kathryn A O'Donnell.
      Mechanisms that control translation play important roles in tumor progression and metastasis. Emerging evidence has revealed that dysregulated translation also impacts immune evasion in response to cellular or oncogenic stress. Here, we summarize current knowledge regarding the translational control of immune checkpoints and implications for cancer immunotherapies.
    Keywords:  PD-1/PD-L1; alternative translation initiation factors; immune checkpoints; integrated stress response (ISR) pathway; translation regulation
    DOI:  https://doi.org/10.1016/j.trecan.2021.04.002
  6. Cancer Res. 2021 May 12. pii: canres.2496.2020. [Epub ahead of print]
    Cancer-associated fibroblasts in pancreatic ductal adenocarcinoma determine response to SLC7A11 inhibition.
    George Sharbeen, Joshua A McCarroll, Anouschka Akerman, Chantal Kopecky, Janet Youkhana, John Kokkinos, Jeff Holst, Cyrille Boyer, Mert Erkan, David Goldstein, Paul Timpson, Thomas R Cox, Brooke A Pereira, Jessica L Chitty, Sigrid K Fey, Arafath K Najumudeen, Andrew D Campbell, Owen J Sansom, Rosa Mistica C Ignacio, Stephanie Naim, Jie Liu, Nelson Russia, Julia Lee, Angela Chou, Amber Johns, Anthony J Gill, Estrella Gonzales-Aloy, Val Gebski, Yi Fang Guan, Marina Pajic, Nigel Turner, Minoti V Apte, Thomas P Davis, Jennifer P Morton, Koroush S Haghighi, Jorjina Kasparian, Benjamin J McLean, Yordanos F I Setargew, Australian Pancreatic Cancer Genome Initiative Apgi, Phoebe A Phillips.
      Cancer-Associated Fibroblasts (CAF) are major contributors to pancreatic ductal adenocarcinoma (PDAC) progression through pro-tumor signaling and the generation of fibrosis that creates a physical barrier to drugs. CAF inhibition is thus an ideal component of any therapeutic approach for PDAC. SLC7A11, a cystine transporter, has been identified as a potential therapeutic target in PDAC cells. However, the role of SLC7A11 in PDAC tumor stroma and its prognostic significance has not been evaluated. Here we show that high expression of SLC7A11 in human PDAC tumor stroma, but not tumor cells, is independently prognostic of poor overall survival. Orthogonal approaches showed that PDAC-derived CAFs were dependent on SLC7A11 for cystine uptake and glutathione synthesis. SLC7A11 inhibition significantly decreased CAF proliferation, reduced their resistance to oxidative stress, and inhibited their ability to remodel collagen and support PDAC cell growth. Specific ablation of SLC7A11 from the tumor compartment of transgenic mice did not affect PDAC growth, suggesting the stroma can substantially influence PDAC response to SLC7A11 inhibition. In an orthotopic PDAC mouse model utilizing human PDAC cells and CAFs, stable knockdown of SLC7A11 was required in both cell types to reduce tumor growth, metastatic spread, and intratumoral fibrosis, demonstrating the importance of targeting SLC7A11 in both compartments. Finally, treatment with a nanoparticle SLC7A11-silencing drug developed by our laboratory reduced PDAC tumor growth, metastasis, CAF activation, and fibrosis in orthotopic PDAC tumors. Overall, these findings identify an important role of SLC7A11 in PDAC-derived CAFs in supporting tumor growth.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-2496
  7. Dev Cell. 2021 May 11. pii: S1534-5807(21)00357-9. [Epub ahead of print]
    PI5P4Ks drive metabolic homeostasis through peroxisome-mitochondria interplay.
    Archna Ravi, Lavinia Palamiuc, Ryan M Loughran, Joanna Triscott, Gurpreet K Arora, Avi Kumar, Vivian Tieu, Chantal Pauli, Matthias Reist, Rachel J Lew, Shauna L Houlihan, Christof Fellmann, Christian Metallo, Mark A Rubin, Brooke M Emerling.
      PI5P4Ks are a class of phosphoinositide kinases that phosphorylate PI-5-P to PI-4,5-P2. Distinct localization of phosphoinositides is fundamental for a multitude of cellular functions. Here, we identify a role for peroxisomal PI-4,5-P2 generated by the PI5P4Ks in maintaining energy balance. We demonstrate that PI-4,5-P2 regulates peroxisomal fatty acid oxidation by mediating trafficking of lipid droplets to peroxisomes, which is essential for sustaining mitochondrial metabolism. Using fluorescent-tagged lipids and metabolite tracing, we show that loss of the PI5P4Ks significantly impairs lipid uptake and β-oxidation in the mitochondria. Further, loss of PI5P4Ks results in dramatic alterations in mitochondrial structural and functional integrity, which under nutrient deprivation is further exacerbated, causing cell death. Notably, inhibition of the PI5P4Ks in cancer cells and mouse tumor models leads to decreased cell viability and tumor growth, respectively. Together, these studies reveal an unexplored role for PI5P4Ks in preserving metabolic homeostasis, which is necessary for tumorigenesis.
    Keywords:  PI-4,5-P(2); PI-5-P; PI5P4Ks; cancer; fatty acid; lipid; lipid droplet; metabolism; mitochondria; peroxisome; phosphoinositide; phosphoinositide kinase; sarcoma; β-oxidation
    DOI:  https://doi.org/10.1016/j.devcel.2021.04.019
  8. Elife. 2021 May 14. pii: e62233. [Epub ahead of print]10
    A TORC1-histone axis regulates chromatin organisation and non-canonical induction of autophagy to ameliorate ageing.
    Yu-Xuan Lu, Jennifer C Regan, Jacqueline Eßer, Lisa F Drews, Thomas Weinseis, Julia Stinn, Oliver Hahn, Richard A Miller, Sebastian Grönke, Linda Partridge.
      Age-related changes to histone levels are seen in many species. However, it is unclear whether changes to histone expression could be exploited to ameliorate the effects of ageing in multicellular organisms. Here we show that inhibition of mTORC1 by the lifespan-extending drug rapamycin increases expression of histones H3 and H4 post-transcriptionally, through eIF3-mediated translation. Elevated expression of H3/H4 in intestinal enterocytes in Drosophila alters chromatin organization, induces intestinal autophagy through transcriptional regulation, prevents age-related decline in the intestine. Importantly, it also mediates rapamycin-induced longevity and intestinal health. Histones H3/H4 regulate expression of an autophagy cargo adaptor Bchs (WDFY3 in mammals), increased expression of which in enterocytes mediates increased H3/H4-dependent healthy longevity. In mice, rapamycin treatment increases expression of histone proteins and Wdfy3 transcription, and alters chromatin organisation in the small intestine, suggesting the mTORC1-histone axis is at least partially conserved in mammals and may offer new targets for anti-ageing interventions.
    Keywords:  D. melanogaster; cell biology; chromosomes; gene expression; mouse
    DOI:  https://doi.org/10.7554/eLife.62233
  9. Elife. 2021 May 13. pii: e64204. [Epub ahead of print]10
    Single-PanIN-seq unveils that ARID1A deficiency promotes pancreatic tumorigenesis by attenuating KRAS-induced senescence.
    Shou Liu, Wenjian Cao, Yichi Niu, Jiayi Luo, Yanhua Zhao, Zhiying Hu, Chenghang Zong.
      ARID1A is one of the most frequently mutated epigenetic regulators in a wide spectrum of cancers. Recent studies have shown that ARID1A deficiency induces global changes in the epigenetic landscape of enhancers and promoters. These broad and complex effects make it challenging to identify the driving mechanisms of ARID1A deficiency in promoting cancer progression. Here, we identified the anti-senescence effect of Arid1a deficiency in the progression of pancreatic intraepithelial neoplasia (PanIN) by profiling the transcriptome of individual PanINs in a mouse model. In a human cell line model, we found that ARID1A deficiency upregulates the expression of Aldehyde Dehydrogenase 1 Family Member A1 (ALDH1A1), which plays an essential role in attenuating the senescence induced by oncogenic KRAS through scavenging reactive oxygen species (ROS). As a subunit of the SWI/SNF chromatin remodeling complex, our ATAC sequencing data showed that ARID1A deficiency increases the accessibility of the enhancer region of ALDH1A1. This study provides the first evidence that ARID1A deficiency promotes pancreatic tumorigenesis by attenuating KRAS-induced senescence through the upregulation of ALDH1A1 expression.
    Keywords:  cancer biology; chromosomes; gene expression; human; mouse
    DOI:  https://doi.org/10.7554/eLife.64204
  10. Nat Commun. 2021 May 11. 12(1): 2622
    Peripheral-specific Y1 receptor antagonism increases thermogenesis and protects against diet-induced obesity.
    Chenxu Yan, Tianshu Zeng, Kailun Lee, Max Nobis, Kim Loh, Luoning Gou, Zefeng Xia, Zhongmin Gao, Mohammed Bensellam, Will Hughes, Jackie Lau, Lei Zhang, Chi Kin Ip, Ronaldo Enriquez, Hanyu Gao, Qiao-Ping Wang, Qi Wu, Jody J Haigh, D Ross Laybutt, Paul Timpson, Herbert Herzog, Yan-Chuan Shi.
      Obesity is caused by an imbalance between food intake and energy expenditure (EE). Here we identify a conserved pathway that links signalling through peripheral Y1 receptors (Y1R) to the control of EE. Selective antagonism of peripheral Y1R, via the non-brain penetrable antagonist BIBO3304, leads to a significant reduction in body weight gain due to enhanced EE thereby reducing fat mass. Specifically thermogenesis in brown adipose tissue (BAT) due to elevated UCP1 is enhanced accompanied by extensive browning of white adipose tissue both in mice and humans. Importantly, selective ablation of Y1R from adipocytes protects against diet-induced obesity. Furthermore, peripheral specific Y1R antagonism also improves glucose homeostasis mainly driven by dynamic changes in Akt activity in BAT. Together, these data suggest that selective peripheral only Y1R antagonism via BIBO3304, or a functional analogue, could be developed as a safer and more effective treatment option to mitigate diet-induced obesity.
    DOI:  https://doi.org/10.1038/s41467-021-22925-3
  11. Dis Model Mech. 2021 Apr 01. pii: dmm048801. [Epub ahead of print]14(4):
    The liver metastatic niche: modelling the extracellular matrix in metastasis.
    James Drew, Laura M Machesky.
      Dissemination of malignant cells from primary tumours to metastatic sites is a key step in cancer progression. Disseminated tumour cells preferentially settle in specific target organs, and the success of such metastases depends on dynamic interactions between cancer cells and the microenvironments they encounter at secondary sites. Two emerging concepts concerning the biology of metastasis are that organ-specific microenvironments influence the fate of disseminated cancer cells, and that cancer cell-extracellular matrix interactions have important roles at all stages of the metastatic cascade. The extracellular matrix is the complex and dynamic non-cellular component of tissues that provides a physical scaffold and conveys essential adhesive and paracrine signals for a tissue's function. Here, we focus on how extracellular matrix dynamics contribute to liver metastases - a common and deadly event. We discuss how matrix components of the healthy and premetastatic liver support early seeding of disseminated cancer cells, and how the matrix derived from both cancer and liver contributes to the changes in niche composition as metastasis progresses. We also highlight the technical developments that are providing new insights into the stochastic, dynamic and multifaceted roles of the liver extracellular matrix in permitting and sustaining metastasis. An understanding of the contribution of the extracellular matrix to different stages of metastasis may well pave the way to targeted and effective therapies against metastatic disease.
    Keywords:  Cancer metastasis; Extracellular matrix; Liver metastasis; Metastatic niche
    DOI:  https://doi.org/10.1242/dmm.048801
  12. Trends Biochem Sci. 2021 May 06. pii: S0968-0004(21)00066-9. [Epub ahead of print]
    Detecting and Rescuing Stalled Ribosomes.
    Matthew C J Yip, Sichen Shao.
      Ribosomes that stall inappropriately during protein synthesis harbor proteotoxic components linked to cellular stress and neurodegenerative diseases. Molecular mechanisms that rescue stalled ribosomes must selectively detect rare aberrant translational complexes and process the heterogeneous components. Ribosome-associated quality control pathways eliminate problematic messenger RNAs and nascent proteins on stalled translational complexes. In addition, recent studies have uncovered general principles of stall recognition upstream of quality control pathways and fail-safe mechanisms that ensure nascent proteome integrity. Here, we discuss developments in our mechanistic understanding of the detection and rescue of stalled ribosomal complexes in eukaryotes.
    Keywords:  ribosome collisions; ribosome stalling; ribosome-associated quality control (RQC)
    DOI:  https://doi.org/10.1016/j.tibs.2021.03.008
  13. Autophagy. 2021 May 08. 1-17
    CREG1 promotes lysosomal biogenesis and function.
    Jie Liu, Yanmei Qi, Joshua Chao, Pranav Sathuvalli, Leonard Y Lee, Shaohua Li.
      CREG1 is a small glycoprotein which has been proposed as a transcription repressor, a secretory ligand, a lysosomal, or a mitochondrial protein. This is largely because of lack of antibodies for immunolocalization validated through gain- and loss-of-function studies. In the present study, we demonstrate, using antibodies validated for immunofluorescence microscopy, that CREG1 is mainly localized to the endosomal-lysosomal compartment. Gain- and loss-of-function analyses reveal an important role for CREG1 in both macropinocytosis and clathrin-dependent endocytosis. CREG1 also promotes acidification of the endosomal-lysosomal compartment and increases lysosomal biogenesis. Functionally, overexpression of CREG1 enhances macroautophagy/autophagy and lysosome-mediated degradation, whereas knockdown or knockout of CREG1 has opposite effects. The function of CREG1 in lysosomal biogenesis is likely attributable to enhanced endocytic trafficking. Our results demonstrate that CREG1 is an endosomal-lysosomal protein implicated in endocytic trafficking and lysosomal biogenesis.Abbreviations: AIFM1/AIF: apoptosis inducing factor mitochondria associated 1; AO: acridine orange; ATP6V1H: ATPase H+ transporting V1 subunit H; CALR: calreticulin; CREG: cellular repressor of E1A stimulated genes; CTSC: cathepsin C; CTSD: cathepsin D; EBAG9/RCAS1: estrogen receptor binding site associated antigen 9; EIPA: 5-(N-ethyl-N-isopropyl)amiloride; ER: endoplasmic reticulum; GFP: green fluorescent protein; HEXA: hexosaminidase subunit alpha; IGF2R: insulin like growth factor 2 receptor; LAMP1: lysosomal associated membrane protein 1; M6PR: mannose-6-phosphate receptor, cation dependent; MAPK1/ERK2: mitogen-activated protein kinase 1; MTORC1: mechanistic target of rapamycin kinase complex 1; PDIA2: protein disulfide isomerase family A member 2; SQSTM1/p62: sequestosome 1; TF: transferrin; TFEB: transcription factor EB.
    Keywords:  Autophagy; endocytosis; gene targeting; hepatocytes; immunofluorescence
    DOI:  https://doi.org/10.1080/15548627.2021.1909997
  14. Cell Rep. 2021 May 11. pii: S2211-1247(21)00435-6. [Epub ahead of print]35(6): 109101
    Chromatin accessibility governs the differential response of cancer and T cells to arginine starvation.
    Nicholas T Crump, Andreas V Hadjinicolaou, Meng Xia, John Walsby-Tickle, Uzi Gileadi, Ji-Li Chen, Mashiko Setshedi, Lars R Olsen, I-Jun Lau, Laura Godfrey, Lynn Quek, Zhanru Yu, Erica Ballabio, Mike B Barnkob, Giorgio Napolitani, Mariolina Salio, Hashem Koohy, Benedikt M Kessler, Stephen Taylor, Paresh Vyas, James S O McCullagh, Thomas A Milne, Vincenzo Cerundolo.
      Depleting the microenvironment of important nutrients such as arginine is a key strategy for immune evasion by cancer cells. Many tumors overexpress arginase, but it is unclear how these cancers, but not T cells, tolerate arginine depletion. In this study, we show that tumor cells synthesize arginine from citrulline by upregulating argininosuccinate synthetase 1 (ASS1). Under arginine starvation, ASS1 transcription is induced by ATF4 and CEBPβ binding to an enhancer within ASS1. T cells cannot induce ASS1, despite the presence of active ATF4 and CEBPβ, as the gene is repressed. Arginine starvation drives global chromatin compaction and repressive histone methylation, which disrupts ATF4/CEBPβ binding and target gene transcription. We find that T cell activation is impaired in arginine-depleted conditions, with significant metabolic perturbation linked to incomplete chromatin remodeling and misregulation of key genes. Our results highlight a T cell behavior mediated by nutritional stress, exploited by cancer cells to enable pathological immune evasion.
    Keywords:  ASS1; ATF4; H3K27me3; T cell chromatin; arginine; cancer metabolism; immunometabolism; immunosuppression; metabolic regulation; nutritional stress
    DOI:  https://doi.org/10.1016/j.celrep.2021.109101
  15. Science. 2021 May 14. 372(6543): 716-721
    Cell-specific transcriptional control of mitochondrial metabolism by TIF1γ drives erythropoiesis.
    Marlies P Rossmann, Karen Hoi, Victoria Chan, Brian J Abraham, Song Yang, James Mullahoo, Malvina Papanastasiou, Ying Wang, Ilaria Elia, Julie R Perlin, Elliott J Hagedorn, Sara Hetzel, Raha Weigert, Sejal Vyas, Partha P Nag, Lucas B Sullivan, Curtis R Warren, Bilguujin Dorjsuren, Eugenia Custo Greig, Isaac Adatto, Chad A Cowan, Stuart L Schreiber, Richard A Young, Alexander Meissner, Marcia C Haigis, Siegfried Hekimi, Steven A Carr, Leonard I Zon.
      Transcription and metabolism both influence cell function, but dedicated transcriptional control of metabolic pathways that regulate cell fate has rarely been defined. We discovered, using a chemical suppressor screen, that inhibition of the pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase (DHODH) rescues erythroid differentiation in bloodless zebrafish moonshine (mon) mutant embryos defective for transcriptional intermediary factor 1 gamma (tif1γ). This rescue depends on the functional link of DHODH to mitochondrial respiration. The transcription elongation factor TIF1γ directly controls coenzyme Q (CoQ) synthesis gene expression. Upon tif1γ loss, CoQ levels are reduced, and a high succinate/α-ketoglutarate ratio leads to increased histone methylation. A CoQ analog rescues mon's bloodless phenotype. These results demonstrate that mitochondrial metabolism is a key output of a lineage transcription factor that drives cell fate decisions in the early blood lineage.
    DOI:  https://doi.org/10.1126/science.aaz2740
  16. Elife. 2021 May 14. pii: e64943. [Epub ahead of print]10
    A subcellular map of the human kinome.
    Haitao Zhang, Xiaolei Cao, Mei Tang, Guoxuan Zhong, Yuan Si, Haidong Li, Feifeng Zhu, Qinghua Liao, Liuju Li, Jianhui Zhao, Jia Feng, Shuaifeng Li, Chenliang Wang, Manuel Kaulich, Fangwei Wang, Liangyi Chen, Li Li, Zongping Xia, Tingbo Liang, Huasong Lu, Xin-Hua Feng, Bin Zhao.
      The human kinome comprises 538 kinases playing essential functions by catalyzing protein phosphorylation. Annotation of subcellular distribution of the kinome greatly facilitates investigation of normal and disease mechanisms. Here, we present Kinome Atlas (KA), an image-based map of the kinome annotated to 10 cellular compartments. 456 epitope-tagged kinases, representing 85% of the human kinome, were expressed in HeLa cells and imaged by immunofluorescent microscopy under a similar condition. KA revealed kinase family-enriched subcellular localizations, and discovered a collection of new kinase localizations at mitochondria, plasma membrane, extracellular space, and other structures. Furthermore, KA demonstrated the role of liquid-liquid phase separation in formation of kinase condensates. Identification of MOK as a mitochondrial kinase revealed its function in cristae dynamics, respiration, and oxidative stress response. Although limited by possible mislocalization due to overexpression or epitope tagging, this subcellular map of the kinome can be used to refine regulatory mechanisms involving protein phosphorylation.
    Keywords:  biochemistry; cell biology; chemical biology; human
    DOI:  https://doi.org/10.7554/eLife.64943
  17. Autophagy. 2021 May 10. 1-2
    PRKA/PKA signals and autophagy: space matters.
    Liliana Felicia Iannucci, Giulietta Di Benedetto, Konstantinos Lefkimmiatis.
      Macroautophagy/autophagy is the cellular process responsible for the elimination and recycling of aggregated proteins and damaged organelles. Whereas autophagy is strictly regulated by several signaling cascades, the link between this process and the subcellular distribution of its regulatory pathways remains to be established. Our recent work suggests that the compartmentalization of PRKA/PKA (protein kinase cAMP-activated) determines its effects on autophagy. We found that increased cAMP levels generate dramatically different PRKA activity "signatures" mainly dependent on the actions of phosphatases and the distribution of the PRKA holoenzymes containing type II regulatory subunits (PRKAR2A and PRKAR2B; RII). In this punctum we discuss how compartmentalized PRKA signaling events are generated and affect the autophagic flux in specific cell types.
    Keywords:  PKA; PRKA; autophagy; cAMP; compartmentalization; phosphatases
    DOI:  https://doi.org/10.1080/15548627.2021.1924501
  18. Clin Exp Metastasis. 2021 May 10.
    Cancer microenvironment and genomics: evolution in process.
    Stanley P Leong, Isaac P Witz, Orit Sagi-Assif, Sivan Izraely, Jonathan Sleeman, Brian Piening, Bernard A Fox, Carlo B Bifulco, Rachel Martini, Lisa Newman, Melissa Davis, Lauren M Sanders, David Haussler, Olena M Vaske, Marlys Witte.
      Cancer heterogeneity is a result of genetic mutations within the cancer cells. Their proliferation is not only driven by autocrine functions but also under the influence of cancer microenvironment, which consists of normal stromal cells such as infiltrating immune cells, cancer-associated fibroblasts, endothelial cells, pericytes, vascular and lymphatic channels. The relationship between cancer cells and cancer microenvironment is a critical one and we are just on the verge to understand it on a molecular level. Cancer microenvironment may serve as a selective force to modulate cancer cells to allow them to evolve into more aggressive clones with ability to invade the lymphatic or vascular channels to spread to regional lymph nodes and distant sites. It is important to understand these steps of cancer evolution within the cancer microenvironment towards invasion so that therapeutic strategies can be developed to control or stop these processes.
    Keywords:  Cancer evolution; Cancer heterogeneity; Cancer metastasis; Cancer microenvironment
    DOI:  https://doi.org/10.1007/s10585-021-10097-9
  19. Nature. 2021 May 12.
    Cross-tissue organization of the fibroblast lineage.
    Matthew B Buechler, Rachana N Pradhan, Akshay T Krishnamurty, Christian Cox, Aslihan Karabacak Calviello, Amber W Wang, Yeqing Angela Yang, Lucinda Tam, Roger Caothien, Merone Roose-Girma, Zora Modrusan, Joseph R Arron, Richard Bourgon, Sören Müller, Shannon J Turley.
      Fibroblasts are non-haematopoietic structural cells that define the architecture of organs, support the homeostasis of tissue-resident cells and have key roles in fibrosis, cancer, autoimmunity and wound healing1. Recent studies have described fibroblast heterogeneity within individual tissues1. However, the field lacks a characterization of fibroblasts at single-cell resolution across tissues in healthy and diseased organs. Here we constructed fibroblast atlases by integrating single-cell transcriptomic data from about 230,000 fibroblasts across 17 tissues, 50 datasets, 11 disease states and 2 species. Mouse fibroblast atlases and a DptIRESCreERT2 knock-in mouse identified two universal fibroblast transcriptional subtypes across tissues. Our analysis suggests that these cells can serve as a reservoir that can yield specialized fibroblasts across a broad range of steady-state tissues and activated fibroblasts in disease. Comparison to an atlas of human fibroblasts from perturbed states showed that fibroblast transcriptional states are conserved between mice and humans, including universal fibroblasts and activated phenotypes associated with pathogenicity in human cancer, fibrosis, arthritis and inflammation. In summary, a cross-species and pan-tissue approach to transcriptomics at single-cell resolution has identified key organizing principles of the fibroblast lineage in health and disease.
    DOI:  https://doi.org/10.1038/s41586-021-03549-5
  20. Immunity. 2021 May 11. pii: S1074-7613(21)00170-9. [Epub ahead of print]54(5): 976-987.e7
    Glycolytic ATP fuels phosphoinositide 3-kinase signaling to support effector T helper 17 cell responses.
    Ke Xu, Na Yin, Min Peng, Efstathios G Stamatiades, Sagar Chhangawala, Amy Shyu, Peng Li, Xian Zhang, Mytrang H Do, Kristelle J Capistrano, Chun Chou, Christina S Leslie, Ming O Li.
      Aerobic glycolysis-the Warburg effect-converts glucose to lactate via the enzyme lactate dehydrogenase A (LDHA) and is a metabolic feature of effector T cells. Cells generate ATP through various mechanisms and Warburg metabolism is comparatively an energy-inefficient glucose catabolism pathway. Here, we examined the effect of ATP generated via aerobic glycolysis in antigen-driven T cell responses. Cd4CreLdhafl/fl mice were resistant to Th17-cell-mediated experimental autoimmune encephalomyelitis and exhibited defective T cell activation, migration, proliferation, and differentiation. LDHA deficiency crippled cellular redox balance and inhibited ATP production, diminishing PI3K-dependent activation of Akt kinase and thereby phosphorylation-mediated inhibition of Foxo1, a transcriptional repressor of T cell activation programs. Th17-cell-specific expression of an Akt-insensitive Foxo1 recapitulated the defects seen in Cd4CreLdhafl/fl mice. Induction of LDHA required PI3K signaling and LDHA deficiency impaired PI3K-catalyzed PIP3 generation. Thus, Warburg metabolism augments glycolytic ATP production, fueling a PI3K-centered positive feedback regulatory circuit that drives effector T cell responses.
    Keywords:  ATP; LDHA; PI3K; Th17 cell; autoimmunity; glycolysis; redox balance
    DOI:  https://doi.org/10.1016/j.immuni.2021.04.008
  21. FEBS J. 2021 May 10.
    Mitochondrial matrix proteases - quality control and beyond.
    Karolina Szczepanowska, Aleksandra Trifunovic.
      To ensure correct function, mitochondria have developed several mechanisms of protein quality control (QC). Protein homeostasis highly relies on chaperones and proteases to maintain proper folding and remove damaged proteins that might otherwise form cell-toxic aggregates. Besides quality control, mitochondrial proteases modulate and regulate many essential functions, such as trafficking, processing, and activation of mitochondrial proteins, mitochondrial dynamics, mitophagy, and apoptosis. Therefore, the impaired function of mitochondrial proteases is associated with various pathological conditions, including cancer, metabolic syndromes, and neurodegenerative disorders. This review recapitulates and discusses the emerging roles of two major proteases of the mitochondrial matrix, LON and ClpXP. Although commonly acknowledge for their protein quality control role, recent advances have uncovered several highly regulated processes controlled by the LON and ClpXP connected to mitochondrial gene expression and respiratory chain function maintenance. Furthermore, both proteases have been lately recognized as potent targets for anti-cancer therapies, and we summarize those findings.
    Keywords:  ClpXP; LONP1; cancer; degradation; metabolism; mitochondria; mitochondrial matrix; mtDNA; proteases; protein quality control; proteolysis; respiratory complexes
    DOI:  https://doi.org/10.1111/febs.15964
  22. Oncology (Williston Park). 2021 May 12. 35(5): 244-248
    Molecular Profiling Practices in Pancreatic Adenocarcinoma: Academic vs Community Physicians.
    Christine Chung, Rachael Galvin, Ella Achenbach, Oliwier Dziadkowiec, Shiraj Sen.
      Background: Pancreatic adenocarcinoma (PDAC) is relatively rare but highly aggressive, with most patients diagnosed once they have metastatic or locally invasive disease. Molecular profiling is being explored as a tool for selecting patients for targeted therapy clinical trials and for assessing whether targeted therapies may be effective in PDAC. Whether molecular profiling is being performed at both academic and community oncology clinics has yet to be examined. Here, we characterized the molecular profiling practice patterns in patients with PDAC in academic versus community practices in Denver, Colorado. Methods: We retrospectively reviewed records of all patients with refractory, metastatic PDAC who were referred to a tertiary clinical trials drug development unit in Denver between 2014 and 2019. Results: Of 77 patients, 41 (55%) were men with a mean age of 65 years (SD, 9.3). Fifty-three patients (69%) were referred from the community and 20 (26%) from academic centers; 4 (5%) were self-referred. A total of 51% received profiling prior to referral; 29 of 50 (58%) were from the community and 10 of 21 (47%) from academic settings. Guardant was the most commonly ordered test (47 of 77; 61%); FoundationOne was the second most common (40 of 77; 52%). Twenty-three of 77 patients (30%) received both Guardant and FoundationOne testing, and 3 of 77 (4%) received Caris MI Profile. One patient received a Mocha assay and another received Ascend/Clarient fluorescence in situ hybridization (FISH). Four patients were self-referred, 2 of whom underwent both Guardant and FoundationOne, 1 who underwent Guardant testing only, and 1 who did not receive any molecular profiling testing. Conclusions: This study characterizes molecular profiling practice patterns in individuals with advanced PDAC who were referred to a tertiary clinical trials drug development unit. Both academic and community physicians were found to order profiling about 50% of the time. Further research is needed to determine impact on clinical trial enrollment and detection of PDAC.
    DOI:  https://doi.org/10.46883/ONC.2021.3505.0244
  23. Semin Cancer Biol. 2021 May 09. pii: S1044-579X(21)00122-X. [Epub ahead of print]
    Slow-Cycling (Dormant) Cancer Cells in Therapy Resistance, Cancer Relapse and Metastasis.
    Sukanya Basu, Yang Dong, Rahul Kumar, Collene Jeter, Dean G Tang.
      It is increasingly appreciated that cancer cell heterogeneity and plasticity constitute major barriers to effective clinical treatments and long-term therapeutic efficacy. Research in the past two decades suggest that virtually all treatment-naive human cancers harbor subsets of cancer cells that possess many of the cardinal features of normal stem cells. Such stem-like cancer cells, operationally defined as cancer stem cells (CSCs), are frequently quiescent and dynamically change and evolve during tumor progression and therapeutic interventions. Intrinsic tumor cell heterogeneity is reflected in a different aspect in that tumors also harbor a population of slow-cycling cells (SCCs) that are not in the proliferative cell cycle and thus are intrinsically refractory to anti-mitotic drugs. In this Perspective, we focus our discussions on SCCs in cancer and on various methodologies that can be employed to enrich and purify SCCs, compare the similarities and differences between SCCs, CSCs and cancer cells undergoing EMT, and present evidence for the involvement of SCCs in surviving anti-neoplastic treatments, mediating tumor relapse, maintaining tumor dormancy and mediating metastatic dissemination. Our discussions make it clear that an in-depth understanding of the biological properties of SCCs in cancer will be instrumental to developing new therapeutic strategies to prevent tumor relapse and distant metastasis.
    Keywords:  Cancer stem cells; Metastasis; Quiescence; Slow-cycling cells; Therapy resistance
    DOI:  https://doi.org/10.1016/j.semcancer.2021.04.021
  24. Nat Rev Immunol. 2021 May 12.
    CD8+ T cell metabolism in infection and cancer.
    Miguel Reina-Campos, Nicole E Scharping, Ananda W Goldrath.
      Cytotoxic CD8+ T cells play a key role in the elimination of intracellular infections and malignant cells and can provide long-term protective immunity. In the response to infection, CD8+ T cell metabolism is coupled to transcriptional, translational and epigenetic changes that are driven by extracellular metabolites and immunological signals. These programmes facilitate the adaptation of CD8+ T cells to the diverse and dynamic metabolic environments encountered in the circulation and in the tissues. In the setting of disease, both cell-intrinsic and cell-extrinsic metabolic cues contribute to CD8+ T cell dysfunction. In addition, changes in whole-body metabolism, whether through voluntary or disease-induced dietary alterations, can influence CD8+ T cell-mediated immunity. Defining the metabolic adaptations of CD8+ T cells in specific tissue environments informs our understanding of how these cells protect against pathogens and tumours and maintain tissue health at barrier sites. Here, we highlight recent findings revealing how metabolic networks enforce specific CD8+ T cell programmes and discuss how metabolism is integrated with CD8+ T cell differentiation and function and determined by environmental cues.
    DOI:  https://doi.org/10.1038/s41577-021-00537-8
  25. Nat Rev Mol Cell Biol. 2021 May 14.
    The principles of directed cell migration.
    Shuvasree SenGupta, Carole A Parent, James E Bear.
      Cells have the ability to respond to various types of environmental cues, and in many cases these cues induce directed cell migration towards or away from these signals. How cells sense these cues and how they transmit that information to the cytoskeletal machinery governing cell translocation is one of the oldest and most challenging problems in biology. Chemotaxis, or migration towards diffusible chemical cues, has been studied for more than a century, but information is just now beginning to emerge about how cells respond to other cues, such as substrate-associated cues during haptotaxis (chemical cues on the surface), durotaxis (mechanical substrate compliance) and topotaxis (geometric features of substrate). Here we propose four common principles, or pillars, that underlie all forms of directed migration. First, a signal must be generated, a process that in physiological environments is much more nuanced than early studies suggested. Second, the signal must be sensed, sometimes by cell surface receptors, but also in ways that are not entirely clear, such as in the case of mechanical cues. Third, the signal has to be transmitted from the sensing modules to the machinery that executes the actual movement, a step that often requires amplification. Fourth, the signal has to be converted into the application of asymmetric force relative to the substrate, which involves mostly the cytoskeleton, but perhaps other players as well. Use of these four pillars has allowed us to compare some of the similarities between different types of directed migration, but also to highlight the remarkable diversity in the mechanisms that cells use to respond to different cues provided by their environment.
    DOI:  https://doi.org/10.1038/s41580-021-00366-6
  26. Adv Exp Med Biol. 2021 ;1269 169-177
    The Warburg Effect: Historical Dogma Versus Current Rationale.
    Peter Vaupel, Gabriele Multhoff.
      Contrary to Warburg's original thesis, accelerated aerobic glycolysis is not a primary and permanent consequence of dysfunctional mitochondria compensating for a poor ATP yield per mole glucose. Instead, the Warburg effect is an essential part of a "selfish" metabolic reprogramming, which results from the interplay between (normoxic or hypoxic) HIF-1 overexpression, oncogene activation (cMyc, Ras), loss of function of tumor suppressors (mutant p53, mutant PTEN, microRNAs and sirtuins with suppressor functions), activated (PI3K/Akt/mTORC1, Ras/Raf/Mek/Erk/c-Myc) or deactivated (AMPK) signaling pathways, components of the tumor microenvironment, and HIF-1 cooperations with epigenetic mechanisms. Molecular and functional processes of the Warburg effect include (a) considerably accelerated glycolytic fluxes; (b) adequate ATP generation per unit time to maintain energy homeostasis; (c) backup and diversion of glycolytic intermediates facilitating the biosynthesis of nucleotides, nonessential amino acids, lipids, and hexosamines; (d) inhibition of pyruvate entry into mitochondria; (e) excessive formation and accumulation of lactate which stimulates tumor growth and suppression of antitumor immunity (in addition, lactate can serve as an energy source for normoxic cancer cells, contributes to extracellular acidosis, and thus drives malignant progression and resistances to conventional therapies); (f) maintenance of the cellular redox homeostasis and low ROS formation; and (g) HIF-1 overexpression, mutant p53, and mutant PTEN which inhibit mitochondrial biogenesis and functions, thus negatively impacting cellular respiration rate. The glycolytic switch is an early event in oncogenesis and primarily supports cell survival. All in all, the Warburg effect, i.e., aerobic glycolysis in the presence of oxygen and - in principle - functioning mitochondria, constitutes a major driver of the cancer progression machinery, resistance to conventional therapies, and - finally - poor patient outcome.
    Keywords:  ATP generation; Aerobic glycolysis; Biosynthesis of macromolecules; Energy homeostasis; Glycolytic phenotype; Glycolytic switch; Lactate accumulation; Metabolic reprogramming; Oncogenesis; Redox homeostasis; Tumor acidosis; Tumor glucose metabolism; Tumor mitochondria; Warburg effect
    DOI:  https://doi.org/10.1007/978-3-030-48238-1_27
  27. Immunol Rev. 2021 May 13.
    The inflammatory speech of fibroblasts.
    Ronen Schuster, Jason S Rockel, Mohit Kapoor, Boris Hinz.
      Activation of fibroblasts is a key event during normal tissue repair after injury and the dysregulated repair processes that result in organ fibrosis. To most researchers, fibroblasts are rather unremarkable spindle-shaped cells embedded in the fibrous collagen matrix of connective tissues and/or deemed useful to perform mechanistic studies with adherent cells in culture. For more than a century, fibroblasts escaped thorough classification due to the lack of specific markers and were treated as the leftovers after all other cells have been identified from a tissue sample. With novel cell lineage tracing and single cell transcriptomics tools, bona fide fibroblasts emerge as only one heterogeneous sub-population of a much larger group of partly overlapping cell types, including mesenchymal stromal cells, fibro-adipogenic progenitor cells, pericytes, and/or perivascular cells. All these cells are activated to contribute to tissue repair after injury and/or chronic inflammation. "Activation" can entail various functions, such as enhanced proliferation, migration, instruction of inflammatory cells, secretion of extracellular matrix proteins and organizing enzymes, and acquisition of a contractile myofibroblast phenotype. We provide our view on the fibroblastic cell types and activation states playing a role during physiological and pathological repair and their crosstalk with inflammatory macrophages. Inflammation and fibrosis of the articular synovium during rheumatoid arthritis and osteoarthritis are used as specific examples to discuss inflammatory fibroblast phenotypes. Ultimately, delineating the precursors and functional roles of activated fibroblastic cells will contribute to better and more specific intervention strategies to treat fibroproliferative and fibrocontractive disorders.
    Keywords:  Myofibroblast; fibroblast lineage; fibrosis; inflammation; macrophage; osteoarthritis; pericyte; rheumatoid arthritis; synovium; tissue repair; wound healing
    DOI:  https://doi.org/10.1111/imr.12971
  28. Mol Metab. 2021 Apr 30. pii: S2212-8778(21)00088-0. [Epub ahead of print] 101243
    Non-canonical NRF2 activation promotes a pro-diabetic shift in hepatic glucose metabolism.
    Pengfei Liu, Matthew Dodson, Hui Li, Cody J Schmidlin, Aryatara Shakya, Yongyi Wei, Joe G N Garcia, Eli Chapman, Pawel R Kiela, Qing-Yu Zhang, Eileen White, Xinxin Ding, Aikseng Ooi, Donna D Zhang.
      NRF2, a transcription factor that regulates cellular redox and metabolic homeostasis, plays a dual role in human disease. It is well known that canonical intermittent NRF2 activation protects against diabetes-induced tissue damage. However, we show herein that in contrast to canonical NRF2 activation, prolonged non-canonical NRF2 activation via p62-mediated sequestration of KEAP1 increases carbohydrate flux through the polyol pathway, resulting in a pro-diabetic shift in glucose homeostasis. Using a combination of wild-type, Nrf2-/-, p62-/-, and Nrf2-/-;p62-/- mice and an arsenic-induced diabetes model, we demonstrate that NRF2 and p62 are essential for promoting insulin resistance and glucose intolerance. Integrated transcriptomic and metabolomic analyses reveal a p62-and NRF2-dependent increase in liver fructose metabolism and gluconeogenesis through the upregulation of four novel NRF2 target genes. In conclusion, our findings reveal a key pro-diabetic role for non-canonical NRF2 activation.
    Keywords:  Diabetes; Liver carbohydrate metabolism; NRF2; Polyol pathway
    DOI:  https://doi.org/10.1016/j.molmet.2021.101243
  29. Science. 2021 May 14. pii: eabc7531. [Epub ahead of print]372(6543):
    A prometastatic splicing program regulated by SNRPA1 interactions with structured RNA elements.
    Lisa Fish, Matvei Khoroshkin, Albertas Navickas, Kristle Garcia, Bruce Culbertson, Benjamin Hänisch, Steven Zhang, Hoang C B Nguyen, Larisa M Soto, Maria Dermit, Faraz K Mardakheh, Henrik Molina, Claudio Alarcón, Hamed S Najafabadi, Hani Goodarzi.
      Aberrant alternative splicing is a hallmark of cancer, yet the underlying regulatory programs that control this process remain largely unknown. Here, we report a systematic effort to decipher the RNA structural code that shapes pathological splicing during breast cancer metastasis. We discovered a previously unknown structural splicing enhancer that is enriched near cassette exons with increased inclusion in highly metastatic cells. We show that the spliceosomal protein small nuclear ribonucleoprotein polypeptide A' (SNRPA1) interacts with these enhancers to promote cassette exon inclusion. This interaction enhances metastatic lung colonization and cancer cell invasion, in part through SNRPA1-mediated regulation of PLEC alternative splicing, which can be counteracted by splicing modulating morpholinos. Our findings establish a noncanonical regulatory role for SNRPA1 as a prometastatic splicing enhancer in breast cancer.
    DOI:  https://doi.org/10.1126/science.abc7531
  30. EMBO J. 2021 May 14. e106412
    ArfGAP1 inhibits mTORC1 lysosomal localization and activation.
    Delong Meng, Qianmei Yang, Chase H Melick, Brenden C Park, Ting-Sung Hsieh, Adna Curukovic, Mi-Hyeon Jeong, Junmei Zhang, Nicholas G James, Jenna L Jewell.
      The mammalian target of rapamycin complex 1 (mTORC1) integrates nutrients, growth factors, stress, and energy status to regulate cell growth and metabolism. Amino acids promote mTORC1 lysosomal localization and subsequent activation. However, the subcellular location or interacting proteins of mTORC1 under amino acid-deficient conditions is not completely understood. Here, we identify ADP-ribosylation factor GTPase-activating protein 1 (ArfGAP1) as a crucial regulator of mTORC1. ArfGAP1 interacts with mTORC1 in the absence of amino acids and inhibits mTORC1 lysosomal localization and activation. Mechanistically, the membrane curvature-sensing amphipathic lipid packing sensor (ALPS) motifs that bind to vesicle membranes are crucial for ArfGAP1 to interact with and regulate mTORC1 activity. Importantly, ArfGAP1 represses cell growth through mTORC1 and is an independent prognostic factor for the overall survival of pancreatic cancer patients. Our study identifies ArfGAP1 as a critical regulator of mTORC1 that functions by preventing the lysosomal transport and activation of mTORC1, with potential for cancer therapeutics.
    Keywords:  ArfGAP1; amino acids; lysosome; mTORC1; vesicle trafficking
    DOI:  https://doi.org/10.15252/embj.2020106412
  31. Hepatobiliary Pancreat Dis Int. 2021 Apr 28. pii: S1499-3872(21)00079-5. [Epub ahead of print]
    Mitochondria: A critical hub for hepatic stellate cells activation during chronic liver diseases: Mitochondria in hepatic stellate cells.
    Devaraj Ezhilarasan.
       BACKGROUND: Upon liver injury, quiescent hepatic stellate cells (qHSCs), reside in the perisinusoidal space, phenotypically transdifferentiate into myofibroblast-like cells (MFBs). The qHSCs in the normal liver are less fibrogenic, migratory, and also have less proliferative potential. However, activated HSCs (aHSCs) are more fibrogenic and have a high migratory and proliferative MFBs phenotype. HSCs activation is a highly energetic process that needs abundant intracellular energy in the form of adenosine triphosphate (ATP) for the synthesis of extracellular matrix (ECM) in the injured liver to substantiate the injury.
    DATA SOURCES: The articles were collected through PubMed and EMBASE using search terms "mitochondria and hepatic stellate cells", "mitochondria and HSCs", "mitochondria and hepatic fibrosis", "mitochondria and liver diseases", and "mitochondria and chronic liver disease", and relevant publications published before September 31, 2020 were included in this review.
    RESULTS: Mitochondria homeostasis is affected during HSCs activation. Mitochondria in aHSCs are highly energetic and are in a high metabolically active state exhibiting increased activity such as glycolysis and respiration. aHSCs have high glycolytic enzymes expression and glycolytic activity induced by Hedgehog (Hh) signaling from injured hepatocytes. Increased glycolysis and aerobic glycolysis (Warburg effect) end-products in aHSCs consequently activate the ECM-related gene expressions. Increased Hh signaling from injured hepatocytes downregulates peroxisome proliferator-activated receptor-γ expression and decreases lipogenesis in aHSCs. Glutaminolysis and tricarboxylic acid cycle liberate ATPs that fuel HSCs to proliferate and produce ECM during their activation.
    CONCLUSIONS: Available studies suggest that mitochondria functions can increase in parallel with HSCs activation. Therefore, mitochondrial modulators should be tested in an elaborate manner to control or prevent the HSCs activation during liver injury to subsequently regress hepatic fibrosis.
    Keywords:  Glutaminolysis; Glycolysis; Hedgehog; Hepatic stellate cells; Myofibroblasts
    DOI:  https://doi.org/10.1016/j.hbpd.2021.04.010
  32. Biochem J. 2021 May 14. 478(9): 1663-1688
    Cancer cachexia: molecular mechanism and pharmacological management.
    Yonghua Li, Huan Jin, Yibing Chen, Ting Huang, Yanjun Mi, Zhengzhi Zou.
      Cancer cachexia often occurs in malignant tumors and is a multifactorial and complex symptom characterized by wasting of skeletal muscle and adipose tissue, resulting in weight loss, poor life quality and shorter survival. The pathogenic mechanism of cancer cachexia is complex, involving a variety of molecular substrates and signal pathways. Advancements in understanding the molecular mechanisms of cancer cachexia have provided a platform for the development of new targeted therapies. Although recent outcomes of early-phase trials have showed that several drugs presented an ideal curative effect, monotherapy cannot be entirely satisfactory in the treatment of cachexia-associated symptoms due to its complex and multifactorial pathogenesis. Therefore, the lack of definitive therapeutic strategies for cancer cachexia emphasizes the need to develop a better understanding of the underlying mechanisms. Increasing evidences show that the progression of cachexia is associated with metabolic alternations, which mainly include excessive energy expenditure, increased proteolysis and mitochondrial dysfunction. In this review, we provided an overview of the key mechanisms of cancer cachexia, with a major focus on muscle atrophy, adipose tissue wasting, anorexia and fatigue and updated the latest progress of pharmacological management of cancer cachexia, thereby further advancing the interventions that can counteract cancer cachexia.
    Keywords:  anorexia; cancer cachexia; fatigue; muscle atrophy; pharmacotherapy
    DOI:  https://doi.org/10.1042/BCJ20201009
  33. Nat Protoc. 2021 May 14.
    High-throughput full-length single-cell RNA-seq automation.
    Lira Mamanova, Zhichao Miao, Ayesha Jinat, Peter Ellis, Lesley Shirley, Sarah A Teichmann.
      Existing protocols for full-length single-cell RNA sequencing produce libraries of high complexity (thousands of distinct genes) with outstanding sensitivity and specificity of transcript quantification. These full-length libraries have the advantage of allowing probing of transcript isoforms, are informative regarding single-nucleotide polymorphisms and allow assembly of the VDJ region of the T- and B-cell-receptor sequences. Since full-length protocols are mostly plate-based at present, they are also suited to profiling cell types where cell numbers are limiting, such as rare cell types during development. A disadvantage of these methods has been the scalability and cost of the experiments, which has limited their popularity as compared with droplet-based and nanowell approaches. Here, we describe an automated protocol for full-length single-cell RNA sequencing, including both an in-house automated Smart-seq2 protocol and a commercial kit-based workflow. The protocols take 3-5 d to complete, depending on the number of plates processed in a batch. We discuss these two protocols in terms of ease of use, equipment requirements, running time, cost per sample and sequencing quality. By benchmarking the lysis buffers, reverse transcription enzymes and their combinations, we have optimized the in-house automated protocol to dramatically reduce its cost. An automated setup can be adopted easily by a competent researcher with basic laboratory skills and no prior automation experience. These pipelines have been employed successfully for several research projects allied with the Human Cell Atlas initiative ( www.humancellatlas.org ).
    DOI:  https://doi.org/10.1038/s41596-021-00523-3
  34. Cell. 2021 Apr 30. pii: S0092-8674(21)00495-5. [Epub ahead of print]
    Neutrophil elastase selectively kills cancer cells and attenuates tumorigenesis.
    Chang Cui, Kasturi Chakraborty, Xu Anna Tang, Guolin Zhou, Kelly Q Schoenfelt, Kristen M Becker, Alexandria Hoffman, Ya-Fang Chang, Ariane Blank, Catherine A Reardon, Hilary A Kenny, Tomas Vaisar, Ernst Lengyel, Geoffrey Greene, Lev Becker.
      Cancer cell genetic variability and similarity to host cells have stymied development of broad anti-cancer therapeutics. Our innate immune system evolved to clear genetically diverse pathogens and limit host toxicity; however, whether/how innate immunity can produce similar effects in cancer is unknown. Here, we show that human, but not murine, neutrophils release catalytically active neutrophil elastase (ELANE) to kill many cancer cell types while sparing non-cancer cells. ELANE proteolytically liberates the CD95 death domain, which interacts with histone H1 isoforms to selectively eradicate cancer cells. ELANE attenuates primary tumor growth and produces a CD8+T cell-mediated abscopal effect to attack distant metastases. Porcine pancreatic elastase (ELANE homolog) resists tumor-derived protease inhibitors and exhibits markedly improved therapeutic efficacy. Altogether, our studies suggest that ELANE kills genetically diverse cancer cells with minimal toxicity to non-cancer cells, raising the possibility of developing it as a broad anti-cancer therapy.
    Keywords:  CD95; cancer; histone H1; neutrophil estate; neutrophils; therapeutics; tumor immunology
    DOI:  https://doi.org/10.1016/j.cell.2021.04.016
  35. Sci Adv. 2021 May;pii: eabg4000. [Epub ahead of print]7(20):
    Cork-in-bottle mechanism of inhibitor binding to mammalian complex I.
    Injae Chung, Riccardo Serreli, Jason B Cross, M Emilia Di Francesco, Joseph R Marszalek, Judy Hirst.
      Mitochondrial complex I (NADH:ubiquinone oxidoreductase), a major contributor of free energy for oxidative phosphorylation, is increasingly recognized as a promising drug target for ischemia-reperfusion injury, metabolic disorders, and various cancers. Several pharmacologically relevant but structurally unrelated small molecules have been identified as specific complex I inhibitors, but their modes of action remain unclear. Here, we present a 3.0-Å resolution cryo-electron microscopy structure of mammalian complex I inhibited by a derivative of IACS-010759, which is currently in clinical development against cancers reliant on oxidative phosphorylation, revealing its unique cork-in-bottle mechanism of inhibition. We combine structural and kinetic analyses to deconvolute cross-species differences in inhibition and identify the structural motif of a "chain" of aromatic rings as a characteristic that promotes inhibition. Our findings provide insights into the importance of π-stacking residues for inhibitor binding in the long substrate-binding channel in complex I and a guide for future biorational drug design.
    DOI:  https://doi.org/10.1126/sciadv.abg4000
  36. J Cancer Res Clin Oncol. 2021 May 13.
    A novel classification of portal venous tumor invasion to predict residual tumor status after surgery in patients with pancreatic neuroendocrine neoplasms.
    Tomotaka Kato, Atsushi Kudo, Yuko Kinowaki, Yoshiya Ishikawa, Shuichi Watanabe, Keiichi Akahoshi, Kosuke Ogawa, Hiroaki Ono, Daisuke Ban, Shinji Tanaka, Minoru Tanabe.
       PURPOSE: To elucidate whether portal venous tumor invasion (PVTI) is a prognostic factor for patients with pancreatic neuroendocrine neoplasms (Pan-NENs).
    METHODS: From 2002 to 2019, 240 patients with Pan-NEN were included to examine prognostic factors. PVTI based on computed tomography (CT) images are classified into four types: no PVTI (Vp0/1), PVTI not invading the superior mesenteric vein (Vp2), PVTI invading the superior mesenteric vein or portal vein (Vp3), and PVTI invading the portal bifurcation (Vp4).
    RESULTS: Simultaneous liver metastases (SLM) determined the overall survival (OS) in 240 patients. The 5-year OS rates with and without SLM were 46% and 92%, respectively (P < 0.001). PVTIs were observed in 56 of the 240 patients (23%). Among such patients, 39, 11, and 6 had Vp2, Vp3, and Vp4, respectively. The 5-year OS rates with and without PVTI were 62% and 82%, respectively (P < 0.001). Severity of PVTI did not decide PFS and OS after R0/1 resection. There was significant difference in the prognoses between Vp0/1 and Vp2-4. In 161 patients without SLM, 21 had PVTI (13%). According to a multivariate analysis, PVTI and Ki-67 index were independent prognostic factors for progression-free survival (PFS) in patients without SLM. The 5-year PFS rates with and without PVTI were 18% and 77%, respectively (P < 0.001). The 5-year OS rates with and without PVTI were 76% and 95%, respectively (P = 0.02). PVTI was associated with tumor functionality, high serum NSE, and high Ki-67 index.
    CONCLUSIONS: PVTI may be a predictor for postoperative recurrence.
    Keywords:  Classification; Pan-NENs; Portal venous tumor invasion; Tumor thrombus
    DOI:  https://doi.org/10.1007/s00432-021-03660-0
  37. Nat Commun. 2021 May 10. 12(1): 2592
    Decoupling epithelial-mesenchymal transitions from stromal profiles by integrative expression analysis.
    Michael Tyler, Itay Tirosh.
      Epithelial-to-mesenchymal transition (EMT) is the most commonly cited mechanism for cancer metastasis, but it is difficult to distinguish from profiles of normal stromal cells in the tumour microenvironment. In this study we use published single cell RNA-seq data to directly compare mesenchymal signatures from cancer and stromal cells. Informed by these comparisons, we developed a computational framework to decouple these two sources of mesenchymal expression profiles using bulk RNA-seq datasets. This deconvolution offers the opportunity to characterise EMT across hundreds of tumours and examine its association with metastasis and other clinical features. With this approach, we find three distinct patterns of EMT, associated with squamous, gynaecological and gastrointestinal cancer types. Surprisingly, in most cancer types, EMT patterns are not associated with increased chance of metastasis, suggesting that other steps in the metastatic cascade may represent the main bottleneck. This work provides a comprehensive evaluation of EMT profiles and their functional significance across hundreds of tumours while circumventing the confounding effect of stromal cells.
    DOI:  https://doi.org/10.1038/s41467-021-22800-1
  38. Autophagy. 2021 May 10. 1-20
    Phosphoregulation of the autophagy machinery by kinases and phosphatases.
    Mariya Licheva, Babu Raman, Claudine Kraft, Fulvio Reggiori.
      Eukaryotic cells use post-translational modifications to diversify and dynamically coordinate the function and properties of protein networks within various cellular processes. For example, the process of autophagy strongly depends on the balanced action of kinases and phosphatases. Highly conserved from the budding yeast Saccharomyces cerevisiae to humans, autophagy is a tightly regulated self-degradation process that is crucial for survival, stress adaptation, maintenance of cellular and organismal homeostasis, and cell differentiation and development. Many studies have emphasized the importance of kinases and phosphatases in the regulation of autophagy and identified many of the core autophagy proteins as their direct targets. In this review, we summarize the current knowledge on kinases and phosphatases acting on the core autophagy machinery and discuss the relevance of phosphoregulation for the overall process of autophagy.
    Keywords:  Autophagosome; PAS; macroautophagy; phagophore; posttranslational modification
    DOI:  https://doi.org/10.1080/15548627.2021.1909407
  39. Cancer Cell. 2020 12 14. pii: S1535-6108(20)30599-7. [Epub ahead of print]38(6): 751-752
    Angelika Amon (1967-2020).
    Charles Swanton.
      
    DOI:  https://doi.org/10.1016/j.ccell.2020.11.007
  40. Genome Biol. 2021 May 13. 22(1): 154
    Multi-omic profiling of lung and liver tumor microenvironments of metastatic pancreatic cancer reveals site-specific immune regulatory pathways.
    Won Jin Ho, Rossin Erbe, Ludmila Danilova, Zaw Phyo, Emma Bigelow, Genevieve Stein-O'Brien, Dwayne L Thomas, Soren Charmsaz, Nicole Gross, Skylar Woolman, Kayla Cruz, Rebecca M Munday, Neeha Zaidi, Todd D Armstrong, Marcelo B Sztein, Mark Yarchoan, Elizabeth D Thompson, Elizabeth M Jaffee, Elana J Fertig.
       BACKGROUND: The majority of pancreatic ductal adenocarcinomas (PDAC) are diagnosed at the metastatic stage, and standard therapies have limited activity with a dismal 5-year survival rate of only 8%. The liver and lung are the most common sites of PDAC metastasis, and each have been differentially associated with prognoses and responses to systemic therapies. A deeper understanding of the molecular and cellular landscape within the tumor microenvironment (TME) metastasis at these different sites is critical to informing future therapeutic strategies against metastatic PDAC.
    RESULTS: By leveraging combined mass cytometry, immunohistochemistry, and RNA sequencing, we identify key regulatory pathways that distinguish the liver and lung TMEs in a preclinical mouse model of metastatic PDAC. We demonstrate that the lung TME generally exhibits higher levels of immune infiltration, immune activation, and pro-immune signaling pathways, whereas multiple immune-suppressive pathways are emphasized in the liver TME. We then perform further validation of these preclinical findings in paired human lung and liver metastatic samples using immunohistochemistry from PDAC rapid autopsy specimens. Finally, in silico validation with transfer learning between our mouse model and TCGA datasets further demonstrates that many of the site-associated features are detectable even in the context of different primary tumors.
    CONCLUSIONS: Determining the distinctive immune-suppressive features in multiple liver and lung TME datasets provides further insight into the tissue specificity of molecular and cellular pathways, suggesting a potential mechanism underlying the discordant clinical responses that are often observed in metastatic diseases.
    DOI:  https://doi.org/10.1186/s13059-021-02363-6
  41. J Gastrointest Oncol. 2021 Apr;12(Suppl 1): S110-S117
    Conversion surgery in patients with pancreatic cancer and peritoneal metastasis.
    Suguru Yamada, Tsutomu Fujii, Tomohisa Yamamoto, Hideki Takami, Isaku Yoshioka, So Yamaki, Fuminori Sonohara, Kazuto Shibuya, Fuyuhiko Motoi, Satoshi Hirano, Yoshiak Murakami, Hitoshi Inoue, Masamichi Hayashi, Daisuke Hashimoto, Kenta Murotani, Joji Kitayama, Hideki Ishikawa, Yasuhiro Kodera, Mitsugu Sekimoto, Sohei Satoi.
       Background: Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies globally. We have previously explored the clinical efficacy of intraperitoneal (IP) paclitaxel therapy for patients with PDAC and peritoneal metastasis, which demonstrated favourable response and disease control rates. However, the real implications of conversion surgery after IP therapy remain unclear.
    Methods: We conducted two multicenter clinical trials of IP therapy with paclitaxel in patients with PDAC and peritoneal metastasis. We focused on patients who underwent conversion surgery and investigated the long-term outcomes, particularly, initial recurrence patterns and long-term survival.
    Results: Seventy-nine patients with PDAC and peritoneal metastasis were treated, and 33 (41.8%) patients received SP (intravenous IP paclitaxel with S-1) and 46 (58.3%) were administered GAP (intravenous gemcitabine + nab-paclitaxel combined with IP paclitaxel) combination therapy. Of the 79 patients, 16 (20.3%) underwent conversion surgery. The median time to surgery was 9.0 (range, 4.1-13.0) months after the initiation of chemotherapy. Finally, 13 (81.3%) patients underwent R0 resection. Evans grade was IIA in nine patients, IIB in four patients, III in two patients, and IV in one patient. The median overall survival time in patients who underwent conversion surgery was 32.5 (range, 13.5-66.9) months. Twelve (75.0%) patients were found to have experienced recurrence after conversion surgery. Especially, peritoneal recurrence was observed in 50% of patients as the initial recurrence pattern. The median recurrence-free survival time was 9.2 (range, 5.1-32.8) months, and three patients have survived without recurrence to date.
    Conclusions: Our IP therapy displays promising clinical efficacy with acceptable tolerability in patients with PDAC and peritoneal metastasis. Although we could observe some super-responders in the cohort, further improvements in IP therapy are warranted.
    Keywords:  Conversion surgery; intraperitoneal therapy (IP therapy); pancreatic cancer; peritoneal metastasis
    DOI:  https://doi.org/10.21037/jgo-20-243
  42. Front Immunol. 2021 ;12 649061
    Identification, Validation, and Utilization of Immune Cells in Pancreatic Ductal Adenocarcinoma Based on Marker Genes.
    Willem de Koning, Diba Latifi, Yunlei Li, Casper H J van Eijck, Andrew P Stubbs, Dana A M Mustafa.
      The immune response affects tumor biological behavior and progression. The specific immune characteristics of pancreatic ductal adenocarcinoma (PDAC) can determine the metastatic abilities of cancerous cells and the survival of patients. Therefore, it is important to characterize the specific immune landscape in PDAC tissue samples, and the effect of various types of therapy on that immune composition. Previously, a set of marker genes was identified to assess the immune cell composition in different types of cancer tissue samples. However, gene expression and subtypes of immune cells may vary across different types of cancers. The aim of this study was to provide a method to identify immune cells specifically in PDAC tissue samples. The method is based on defining a specific set of marker genes expressed by various immune cells in PDAC samples. A total of 90 marker genes were selected and tested for immune cell type-specific definition in PDAC; including 43 previously used, and 47 newly selected marker genes. The immune cell-type specificity was checked mathematically by calculating the "pairwise similarity" for all candidate genes using the PDAC RNA-sequenced dataset available at The Cancer Genome Atlas. A set of 55 marker genes that identify 22 different immune cell types for PDAC was created. To validate the method and the set of marker genes, an independent mRNA expression dataset of 24 samples of PDAC patients who received various types of (neo)adjuvant treatments was used. The results showed that by applying our method we were able to identify PDAC specific marker genes to characterize immune cell infiltration in tissue samples. The method we described enabled identifying different subtypes of immune cells that were affected by various types of therapy in PDAC patients. In addition, our method can be easily adapted and applied to identify the specific immune landscape in various types of tissue samples.
    Keywords:  immune cells; immune microenvironment; mRNA expression; marker genes; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.3389/fimmu.2021.649061
  43. Nat Immunol. 2021 May 13.
    Hallmarks of T cell aging.
    Maria Mittelbrunn, Guido Kroemer.
      The aged adaptive immune system is characterized by progressive dysfunction as well as increased autoimmunity. This decline is responsible for elevated susceptibility to infection and cancer, as well as decreased vaccination efficacy. Recent evidence indicates that CD4+ T cell-intrinsic alteratins contribute to chronic inflammation and are sufficient to accelerate an organism-wide aging phenotype, supporting the idea that T cell aging plays a major role in body-wide deterioration. In this Review, we propose ten molecular hallmarks to represent common denominators of T cell aging. These hallmarks are grouped into four primary hallmarks (thymic involution, mitochondrial dysfunction, genetic and epigenetic alterations, and loss of proteostasis) and four secondary hallmarks (reduction of the TCR repertoire, naive-memory imbalance, T cell senescence, and lack of effector plasticity), and together they explain the manifestation of the two integrative hallmarks (immunodeficiency and inflammaging). A major challenge now is weighing the relative impact of these hallmarks on T cell aging and understanding their interconnections, with the final goal of defining molecular targets for interventions in the aging process.
    DOI:  https://doi.org/10.1038/s41590-021-00927-z
  44. Elife. 2021 May 11. pii: e59696. [Epub ahead of print]10
    Limited inhibition of multiple nodes in a driver network blocks metastasis.
    Ali Ekrem Yesilkanal, Dongbo Yang, Andrea Valdespino, Payal Tiwari, Alan U Sabino, Long Chi Nguyen, Jiyoung Lee, Xiao-He Xie, Siqi Sun, Christopher Dann, Lydia Robinson-Mailman, Ethan Steinberg, Timothy Stuhlmiller, Casey Frankenberger, Elizabeth Goldsmith, Gary L Johnson, Alexandre F Ramos, Marsha R Rosner.
      Metastasis suppression by high-dose, multi-drug targeting is unsuccessful due to network heterogeneity and compensatory network activation. Here we show that targeting driver network signaling capacity by limited inhibition of core pathways is a more effective anti-metastatic strategy. This principle underlies the action of a physiological metastasis suppressor, Raf Kinase Inhibitory Protein (RKIP), that moderately decreases stress-regulated MAP kinase network activity, reducing output to transcription factors such as pro-metastastic BACH1 and motility-related target genes. We developed a low-dose four-drug mimic that blocks metastatic colonization in mouse breast cancer models and increases survival. Experiments and network flow modeling show limited inhibition of multiple pathways is required to overcome variation in MAPK network topology and suppress signaling output across heterogeneous tumor cells. Restricting inhibition of individual kinases dissipates surplus signal, preventing threshold activation of compensatory kinase networks. This low-dose multi-drug approach to decrease signaling capacity of driver networks represents a transformative, clinically-relevant strategy for anti-metastatic treatment.
    Keywords:  cancer biology; human; mouse
    DOI:  https://doi.org/10.7554/eLife.59696
  45. STAR Protoc. 2021 Jun 18. 2(2): 100483
    Integrative modeling identifies genetic ancestry-associated molecular correlates in human cancer.
    A Gordon Robertson, Christina Yau, Jian Carrot-Zhang, Jeffrey S Damrauer, Theo A Knijnenburg, Nyasha Chambwe, Katherine A Hoadley, Anab Kemal, Jean C Zenklusen, Andrew D Cherniack, Rameen Beroukhim, Wanding Zhou.
      Cellular and molecular aberrations contribute to the disparity of human cancer incidence and etiology between ancestry groups. Multiomics profiling in The Cancer Genome Atlas (TCGA) allows for querying of the molecular underpinnings of ancestry-specific discrepancies in human cancer. Here, we provide a protocol for integrative associative analysis of ancestry with molecular correlates, including somatic mutations, DNA methylation, mRNA transcription, miRNA transcription, and pathway activity, using TCGA data. This protocol can be generalized to analyze other cancer cohorts and human diseases. For complete details on the use and execution of this protocol, please refer to Carrot-Zhang et al. (2020).
    Keywords:  Bioinformatics; Cancer; Genomics
    DOI:  https://doi.org/10.1016/j.xpro.2021.100483
  46. Nat Commun. 2021 May 11. 12(1): 2656
    Selective and noncovalent targeting of RAS mutants for inhibition and degradation.
    Kai Wen Teng, Steven T Tsai, Takamitsu Hattori, Carmine Fedele, Akiko Koide, Chao Yang, Xuben Hou, Yingkai Zhang, Benjamin G Neel, John P O'Bryan, Shohei Koide.
      Activating mutants of RAS are commonly found in human cancers, but to date selective targeting of RAS in the clinic has been limited to KRAS(G12C) through covalent inhibitors. Here, we report a monobody, termed 12VC1, that recognizes the active state of both KRAS(G12V) and KRAS(G12C) up to 400-times more tightly than wild-type KRAS. The crystal structures reveal that 12VC1 recognizes the mutations through a shallow pocket, and 12VC1 competes against RAS-effector interaction. When expressed intracellularly, 12VC1 potently inhibits ERK activation and the proliferation of RAS-driven cancer cell lines in vitro and in mouse xenograft models. 12VC1 fused to VHL selectively degrades the KRAS mutants and provides more extended suppression of mutant RAS activity than inhibition by 12VC1 alone. These results demonstrate the feasibility of selective targeting and degradation of KRAS mutants in the active state with noncovalent reagents and provide a starting point for designing noncovalent therapeutics against oncogenic RAS mutants.
    DOI:  https://doi.org/10.1038/s41467-021-22969-5
  47. Front Cell Dev Biol. 2021 ;9 654337
    Interplay Between Glucose Metabolism and Chromatin Modifications in Cancer.
    Rui Ma, Yinsheng Wu, Shanshan Li, Xilan Yu.
      Cancer cells reprogram glucose metabolism to meet their malignant proliferation needs and survival under a variety of stress conditions. The prominent metabolic reprogram is aerobic glycolysis, which can help cells accumulate precursors for biosynthesis of macromolecules. In addition to glycolysis, recent studies show that gluconeogenesis and TCA cycle play important roles in tumorigenesis. Here, we provide a comprehensive review about the role of glycolysis, gluconeogenesis, and TCA cycle in tumorigenesis with an emphasis on revealing the novel functions of the relevant enzymes and metabolites. These functions include regulation of cell metabolism, gene expression, cell apoptosis and autophagy. We also summarize the effect of glucose metabolism on chromatin modifications and how this relationship leads to cancer development. Understanding the link between cancer cell metabolism and chromatin modifications will help develop more effective cancer treatments.
    Keywords:  epigenetic modifications; gene transcription; histone modifications; metabolism; tumorigenesis
    DOI:  https://doi.org/10.3389/fcell.2021.654337
  48. J Cell Sci. 2022 Mar 01. pii: jcs252353. [Epub ahead of print]135(5):
    Dissecting lipid droplet biology with coherent Raman scattering microscopy.
    Tao Chen, Ahmet Yavuz, Meng C Wang.
      Lipid droplets (LDs) are lipid-rich organelles universally found in most cells. They serve as a key energy reservoir, actively participate in signal transduction and dynamically communicate with other organelles. LD dysfunction has been associated with a variety of diseases. The content level, composition and mobility of LDs are crucial for their physiological and pathological functions, and these different parameters of LDs are subject to regulation by genetic factors and environmental inputs. Coherent Raman scattering (CRS) microscopy utilizes optical nonlinear processes to probe the intrinsic chemical bond vibration, offering label-free, quantitative imaging of lipids in vivo with high chemical specificity and spatiotemporal resolution. In this Review, we provide an overview over the principle of CRS microscopy and its application in tracking different parameters of LDs in live cells and organisms. We also discuss the use of CRS microscopy in genetic screens to discover lipid regulatory mechanisms and in understanding disease-related lipid pathology.
    Keywords:  Coherent Raman scattering microscopy; Genetic screens; Label-free imaging; Lipid droplet; Lipid metabolism
    DOI:  https://doi.org/10.1242/jcs.252353
  49. Sci Adv. 2021 May;pii: eabd1505. [Epub ahead of print]7(20):
    Noninvasive visualization of electrical conductivity in tissues at the micrometer scale.
    Yuanhui Huang, Murad Omar, Weili Tian, Hernán Lopez-Schier, Gil Gregor Westmeyer, Andriy Chmyrov, George Sergiadis, Vasilis Ntziachristos.
      Despite its importance in regulating cellular or tissue function, electrical conductivity can only be visualized in tissue indirectly as voltage potentials using fluorescent techniques, or directly with radio waves. These either requires invasive procedures like genetic modification or suffers from limited resolution. Here, we introduce radio-frequency thermoacoustic mesoscopy (RThAM) for the noninvasive imaging of conductivity by exploiting the direct absorption of near-field ultrashort radio-frequency pulses to stimulate the emission of broadband ultrasound waves. Detection of ultrasound rather than radio waves enables micrometer-scale resolutions, over several millimeters of tissue depth. We confirm an imaging resolution of <30 μm in phantoms and demonstrate microscopic imaging of conductivity correlating to physical structures in 1- and 512-cell zebrafish embryos, as well as larvae. These results support RThAM as a promising method for high-resolution, label-free assessment of conductivity in tissues.
    DOI:  https://doi.org/10.1126/sciadv.abd1505
  50. Biophys J. 2021 May 05. pii: S0006-3495(21)00374-X. [Epub ahead of print]
    Imaging developmental cell cycles.
    Abraham Q Kohrman, Rebecca P Kim-Yip, Eszter Posfai.
      The last decade has seen a major expansion in development of live biosensors, the tools needed to genetically encode them into model organisms, and the microscopic techniques used to visualize them. When combined, these offer us powerful tools with which to make fundamental discoveries about complex biological processes. In this review we summarize the availability of biosensors to visualize an essential cellular process-the cell cycle-and the techniques for single cell tracking and quantification of these reporters. We also highlight studies investigating the connection of cellular behavior to the cell cycle, particularly through live imaging, and anticipate exciting discoveries with the combination of these technologies in developmental contexts.
    DOI:  https://doi.org/10.1016/j.bpj.2021.04.035
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