bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2022‒09‒25
34 papers selected by
Kıvanç Görgülü
Technical University of Munich
  1. Targeting of biomolecular condensates to the autophagy pathway.
  2. Sensitisation of cancer cells to radiotherapy by serine and glycine starvation.
  3. Characterization of cellular senescence in aging skeletal muscle.
  4. Tumor Microenvironment in Pancreatic Cancer Pathogenesis and Therapeutic Resistance.
  5. Reduced endosomal microautophagy activity in aging associates with enhanced exocyst-mediated protein secretion.
  6. Immunohistochemical Detection of the Autophagy Markers LC3 and p62/SQSTM1 in Formalin-Fixed and Paraffin-Embedded Tissue.
  7. Mechanisms of PDAC subtype heterogeneity and therapy response.
  8. Targeting cellular senescence in metabolic disease.
  9. CLN3 is required for the clearance of glycerophosphodiesters from lysosomes.
  10. Current Screening Strategies for Pancreatic Cancer.
  11. Phosphatidylethanolamine N-Methyltransferase Knockout Modulates Metabolic Changes in Aging Mice.
  12. Emerging Implications of Phase Separation in Cancer.
  13. Towards precision oncology with patient-derived xenografts.
  14. Neoadjuvant chemotherapy is associated with altered immune cell infiltration and an anti-tumorigenic microenvironment in resected pancreatic cancer.
  15. A cellular hierarchy in melanoma uncouples growth and metastasis.
  16. In situ structural analysis reveals membrane shape transitions during autophagosome formation.
  17. Mechanobiology of solid tumors.
  18. Emerging Roles of Lipophagy in Cancer Metastasis.
  19. Novel Regulators of Macropinocytosis-Dependent Growth Revealed by Informer Set Library Screening in Pancreatic Cancer Cells.
  20. Proteogenomic analysis of cancer aneuploidy and normal tissues reveals divergent modes of gene regulation across cellular pathways.
  21. Mechanisms of Basement Membrane Micro-Perforation during Cancer Cell Invasion into a 3D Collagen Gel.
  22. Improving the reproducibility of metabolic research.
  23. Muscle wasting in cancer: opportunities and challenges for exercise in clinical cancer trials.
  24. Lysosome Imaging Based on Fluorescent Carbon Dots.
  25. Artificial intelligence in histopathology: enhancing cancer research and clinical oncology.
  26. Oxygen regulation of breathing is abolished in mitochondrial complex III-deficient arterial chemoreceptors.
  27. Fluorescent Biosensor for Measuring Ras Activity in Living Cells.
  28. Cell Rover-a miniaturized magnetostrictive antenna for wireless operation inside living cells.
  29. Protein condensation diseases: therapeutic opportunities.
  30. Exercise as cancer treatment: A clinical oncology framework for exercise oncology research.
  31. A protocol for mimicking lipid-mediated phase separation on the membrane using giant unilamellar vesicles.
  32. A Mitofusin 2 - Hif1α axis sets a maturation checkpoint in regenerating skeletal muscle.
  33. Telomeres to go.
  34. Empirical single-cell tracking and cell-fate simulation reveal dual roles of p53 in tumor suppression.
  1. Trends Cell Biol. 2022 Sep 20. pii: S0962-8924(22)00208-2. [Epub ahead of print]
    Targeting of biomolecular condensates to the autophagy pathway.
    Xinyu Ma, Pilong Li, Liang Ge.
      Biomolecular condensates are membraneless compartments formed by liquid-liquid phase separation. They can phase transit into gel-like and solid states. The amount and state of biomolecular condensates must be tightly regulated to maintain normal cellular function. Autophagy targets biomolecular condensates to the lysosome for degradation or other purposes, which we term biocondensophagy. In biocondensophagy, autophagy receptors recognize biomolecular condensates and target them to the autophagosome, the vesicle carrier of autophagy. Multiple types of autophagy receptors have been identified and they are specifically involved in targeting biomolecular condensates with different phase transition states. The receptors also organize the phase transition of biomolecular condensate to facilitate biocondensophagy. Here, we briefly discuss the latest discoveries regarding how biomolecular condensates are recognized by autophagy receptors.
    Keywords:  aggrephagy; autophagy; autophagy receptor; biocondensophagy; biomolecular condensate; phase separation; ubiquitin
    DOI:  https://doi.org/10.1016/j.tcb.2022.08.006
  2. Br J Cancer. 2022 Sep 17.
    Sensitisation of cancer cells to radiotherapy by serine and glycine starvation.
    Mattia Falcone, Alejandro Huerta Uribe, Vasileios Papalazarou, Alice C Newman, Dimitris Athineos, Katrina Stevenson, Charles-Etienne Gabriel Sauvé, Yajing Gao, Jin K Kim, Michael Del Latto, Maria Kierstead, Chao Wu, J Joshua Smith, Paul B Romesser, Anthony J Chalmers, Karen Blyth, Oliver D K Maddocks.
      BACKGROUND: Cellular metabolism is an integral component of cellular adaptation to stress, playing a pivotal role in the resistance of cancer cells to various treatment modalities, including radiotherapy. In response to radiotherapy, cancer cells engage antioxidant and DNA repair mechanisms which mitigate and remove DNA damage, facilitating cancer cell survival. Given the reliance of these resistance mechanisms on amino acid metabolism, we hypothesised that controlling the exogenous availability of the non-essential amino acids serine and glycine would radiosensitise cancer cells.METHODS: We exposed colorectal, breast and pancreatic cancer cell lines/organoids to radiation in vitro and in vivo in the presence and absence of exogenous serine and glycine. We performed phenotypic assays for DNA damage, cell cycle, ROS levels and cell death, combined with a high-resolution untargeted LCMS metabolomics and RNA-Seq.
    RESULTS: Serine and glycine restriction sensitised a range of cancer cell lines, patient-derived organoids and syngeneic mouse tumour models to radiotherapy. Comprehensive metabolomic and transcriptomic analysis of central carbon metabolism revealed that amino acid restriction impacted not only antioxidant response and nucleotide synthesis but had a marked inhibitory effect on the TCA cycle.
    CONCLUSION: Dietary restriction of serine and glycine is a viable radio-sensitisation strategy in cancer.
    DOI:  https://doi.org/10.1038/s41416-022-01965-6
  3. Nat Aging. 2022 Jul;2(7): 601-615
    Characterization of cellular senescence in aging skeletal muscle.
    Xu Zhang, Leena Habiballa, Zaira Aversa, Yan Er Ng, Ayumi E Sakamoto, Davis A Englund, Vesselina M Pearsall, Thomas A White, Matthew M Robinson, Donato A Rivas, Surendra Dasari, Adam J Hruby, Anthony B Lagnado, Sarah K Jachim, Antoneta Granic, Avan A Sayer, Diana Jurk, Ian R Lanza, Sundeep Khosla, Roger A Fielding, K Sreekumaran Nair, Marissa J Schafer, João F Passos, Nathan K LeBrasseur.
      Senescence is a cell fate that contributes to multiple aging-related pathologies. Despite profound age-associated changes in skeletal muscle (SkM), whether its constituent cells are prone to senesce has not been methodically examined. Herein, using single cell and bulk RNA-sequencing and complementary imaging methods on SkM of young and old mice, we demonstrate that a subpopulation of old fibroadipogenic progenitors highly expresses p16 Ink4a together with multiple senescence-related genes and, concomitantly, exhibits DNA damage and chromatin reorganization. Through analysis of isolated myofibers, we also detail a senescence phenotype within a subset of old cells, governed instead by p2 Cip1 . Administration of a senotherapeutic intervention to old mice countered age-related molecular and morphological changes and improved SkM strength. Finally, we found that the senescence phenotype is conserved in SkM from older humans. Collectively, our data provide compelling evidence for cellular senescence as a hallmark and potentially tractable mediator of SkM aging.
    DOI:  https://doi.org/10.1038/s43587-022-00250-8
  4. Annu Rev Pathol. 2022 Sep 21.
    Tumor Microenvironment in Pancreatic Cancer Pathogenesis and Therapeutic Resistance.
    Mara H Sherman, Gregory L Beatty.
      Pancreatic ductal adenocarcinoma (PDAC) features a prominent stromal microenvironment with remarkable cellular and spatial heterogeneity that meaningfully impacts disease biology and treatment resistance. Recent advances in tissue imaging capabilities, single-cell analytics, and disease modeling have shed light on organizing principles that shape the stromal complexity of PDAC tumors. These insights into the functional and spatial dependencies that coordinate cancer cell biology and the relationships that exist between cells and extracellular matrix components present in tumors are expected to unveil therapeutic vulnerabilities. We review recent advances in the field and discuss current understandings of mechanisms by which the tumor microenvironment shapes PDAC pathogenesis and therapy resistance. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 18 is January 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-pathmechdis-031621-024600
  5. Aging Cell. 2022 Sep 18. e13713
    Reduced endosomal microautophagy activity in aging associates with enhanced exocyst-mediated protein secretion.
    Gregory J Krause, Antonio Diaz, Maryam Jafari, Rabia R Khawaja, Esperanza Agullo-Pascual, Olaya Santiago-Fernández, Alicia L Richards, Kuei-Ho Chen, Phillip Dmitriev, Yan Sun, Stephanie K See, Kotb Abdelmohsen, Krystyna Mazan-Mamczarz, Nevan J Krogan, Myriam Gorospe, Danielle L Swaney, Simone Sidoli, Jose Javier Bravo-Cordero, Martin Kampmann, Ana Maria Cuervo.
      Autophagy is essential for protein quality control and regulation of the functional proteome. Failure of autophagy pathways with age contributes to loss of proteostasis in aged organisms and accelerates the progression of age-related diseases. In this work, we show that activity of endosomal microautophagy (eMI), a selective type of autophagy occurring in late endosomes, declines with age and identify the sub-proteome affected by this loss of function. Proteomics of late endosomes from old mice revealed an aberrant glycation signature for Hsc70, the chaperone responsible for substrate targeting to eMI. Age-related Hsc70 glycation reduces its stability in late endosomes by favoring its organization into high molecular weight protein complexes and promoting its internalization/degradation inside late endosomes. Reduction of eMI with age associates with an increase in protein secretion, as late endosomes can release protein-loaded exosomes upon plasma membrane fusion. Our search for molecular mediators of the eMI/secretion switch identified the exocyst-RalA complex, known for its role in exocytosis, as a novel physiological eMI inhibitor that interacts with Hsc70 and acts directly at the late endosome membrane. This inhibitory function along with the higher exocyst-RalA complex levels detected in late endosomes from old mice could explain, at least in part, reduced eMI activity with age. Interaction of Hsc70 with components of the exocyst-RalA complex places this chaperone in the switch from eMI to secretion. Reduced intracellular degradation in favor of extracellular release of undegraded material with age may be relevant to the spreading of proteotoxicity associated with aging and progression of proteinopathies.
    Keywords:  aging; autophagy; chaperones; endosomal microautophagy; exocyst complex; late endosomes; protein secretion; proteostasis
    DOI:  https://doi.org/10.1111/acel.13713
  6. Methods Mol Biol. 2023 ;2566 133-139
    Immunohistochemical Detection of the Autophagy Markers LC3 and p62/SQSTM1 in Formalin-Fixed and Paraffin-Embedded Tissue.
    Sabina Berezowska, José A Galván.
      Autophagy is a highly conserved cellular mechanism of "self-digestion," ensuring cellular homeostasis and playing a role in many diseases including cancer. As a stress response mechanism, it may also be involved in cellular response to therapy. LC3 and Sequestosome 1 (p62/SQSTM1) are among the most widely used markers to monitor autophagy and can be visualized in formalin-fixed and paraffin-embedded tissue by immunohistochemistry. Here we describe a validated staining protocol using an automated staining system available in many routine pathology laboratories, enabling high-throughput staining under standardized conditions.
    Keywords:  Autophagy; Immunohistochemistry; LC3; Sequestosome 1; p62/SQSTM1
    DOI:  https://doi.org/10.1007/978-1-0716-2675-7_10
  7. Trends Cancer. 2022 Sep 15. pii: S2405-8033(22)00188-1. [Epub ahead of print]
    Mechanisms of PDAC subtype heterogeneity and therapy response.
    Elisa Espinet, Lukas Klein, Ellen Puré, Shiv K Singh.
      Pancreatic ductal adenocarcinoma (PDAC) is clinically challenging due to late diagnosis and resistance to therapy. Two major PDAC subtypes have been defined based on malignant epithelial cell gene expression profiles; the basal-like/squamous subtype is associated with a worse prognosis and therapeutic resistance as opposed to the classical subtype. Subtype specification is not binary, consistent with plasticity of malignant cell phenotype. PDAC heterogeneity and plasticity reflect partly malignant cell-intrinsic transcriptional and epigenetic regulation. However, the stromal and immune compartments of the tumor microenvironment (TME) also determine disease progression and therapy response. It is evident that integration of intrinsic and extrinsic factors can dictate subtype heterogeneity, and thus, delineating the pathways involved can help to reprogram PDAC towards a classical/druggable subtype.
    Keywords:  CAFs; cytokines; immune cells; pancreatic cancer; subtypes; transcription factors; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.trecan.2022.08.005
  8. Mol Metab. 2022 Sep 16. pii: S2212-8778(22)00170-3. [Epub ahead of print] 101601
    Targeting cellular senescence in metabolic disease.
    Allyson K Palmer, Tamar Tchkonia, James L Kirkland.
      Cellular senescence is a cell fate involving cell cycle arrest, resistance against apoptosis, and the development of a secretome that can be pro-inflammatory. In aging and obesity, senescent cells accumulate in many tissues, including adipose tissue, brain, kidney, pancreas, and liver. These senescent cells and their downstream effects appear to perpetuate inflammation and have been implicated in the pathogenesis of metabolic dysfunction. Senescent cells are cleared in part by the immune system, a process that is diminished in obesity and aging, likely due in part to senescence of immune cells themselves. Targeting senescent cells or their products improves metabolic function in both aging and in animal models of obesity. Novel therapeutics to target senescent cells are on the horizon and are currently being investigated in clinical trials in humans for multiple diseases. Early evidence suggests that senolytic drugs, which transiently disarm the anti-apoptotic defenses of pro-inflammatory senescent cells, are effective in causing depletion of senescent cells in humans. Senescence-targeting therapeutics, including senolytic drugs and strategies to increase immune clearance of senescent cells, hold significant promise for treating metabolic dysfunction in multiple tissues and disease states.
    Keywords:  Adipose; Aging; Cellular senescence; Obesity; Senolytics
    DOI:  https://doi.org/10.1016/j.molmet.2022.101601
  9. Nature. 2022 Sep 21.
    CLN3 is required for the clearance of glycerophosphodiesters from lysosomes.
    Nouf N Laqtom, Wentao Dong, Uche N Medoh, Andrew L Cangelosi, Vimisha Dharamdasani, Sze Ham Chan, Tenzin Kunchok, Caroline A Lewis, Ivonne Heinze, Rachel Tang, Christian Grimm, An N Dang Do, Forbes D Porter, Alessandro Ori, David M Sabatini, Monther Abu-Remaileh.
      Lysosomes have many roles, including degrading macromolecules and signalling to the nucleus1. Lysosomal dysfunction occurs in various human conditions, such as common neurodegenerative diseases and monogenic lysosomal storage disorders (LSDs)2-4. For most LSDs, the causal genes have been identified but, in some, the function of the implicated gene is unknown, in part because lysosomes occupy a small fraction of the cellular volume so that changes in lysosomal contents are difficult to detect. Here we develop the LysoTag mouse for the tissue-specific isolation of intact lysosomes that are compatible with the multimodal profiling of their contents. We used the LysoTag mouse to study CLN3, a lysosomal transmembrane protein with an unknown function. In children, the loss of CLN3 causes juvenile neuronal ceroid lipofuscinosis (Batten disease), a lethal neurodegenerative LSD. Untargeted metabolite profiling of lysosomes from the brains of mice lacking CLN3 revealed a massive accumulation of glycerophosphodiesters (GPDs)-the end products of glycerophospholipid catabolism. GPDs also accumulate in the lysosomes of CLN3-deficient cultured cells and we show that CLN3 is required for their lysosomal egress. Loss of CLN3 also disrupts glycerophospholipid catabolism in the lysosome. Finally, we found elevated levels of glycerophosphoinositol in the cerebrospinal fluid of patients with Batten disease, suggesting the potential use of glycerophosphoinositol as a disease biomarker. Our results show that CLN3 is required for the lysosomal clearance of GPDs and reveal Batten disease as a neurodegenerative LSD with a defect in glycerophospholipid metabolism.
    DOI:  https://doi.org/10.1038/s41586-022-05221-y
  10. Biomedicines. 2022 Aug 23. pii: 2056. [Epub ahead of print]10(9):
    Current Screening Strategies for Pancreatic Cancer.
    Petr Vanek, Ondrej Urban, Vincent Zoundjiekpon, Premysl Falt.
      Pancreatic ductal adenocarcinoma (PDAC) is a dreaded malignancy with a dismal 5-year survival rate despite maximal efforts on optimizing treatment strategies. Radical surgery is the only potential curative procedure. Unfortunately, the majority of patients are diagnosed with locally advanced or metastatic disease, which renders them ineligible for curative resection. Early detection of PDAC is thus considered to be the most effective way to improve survival. In this regard, pancreatic screening has been proposed to improve results by detecting asymptomatic stages of PDAC and its precursors. There is now evidence of benefits of systematic surveillance in high-risk individuals, and the current guidelines emphasize the potential of screening to affect overall survival in individuals with genetic susceptibility syndromes or familial occurrence of PDAC. Here we aim to summarize the current knowledge about screening strategies for PDAC, including the latest epidemiological data, risk factors, associated hereditary syndromes, available screening modalities, benefits, limitations, as well as management implications.
    Keywords:  diagnosis; hereditary pancreatic cancer; pancreas; pancreatic cancer; pancreatic ductal adenocarcinoma; screening
    DOI:  https://doi.org/10.3390/biomedicines10092056
  11. Biomolecules. 2022 Sep 09. pii: 1270. [Epub ahead of print]12(9):
    Phosphatidylethanolamine N-Methyltransferase Knockout Modulates Metabolic Changes in Aging Mice.
    Qishun Zhou, Fangrong Zhang, Jakob Kerbl-Knapp, Melanie Korbelius, Katharina Barbara Kuentzel, Nemanja Vujić, Alena Akhmetshina, Gerd Hörl, Margret Paar, Ernst Steyrer, Dagmar Kratky, Tobias Madl.
      Phospholipid metabolism, including phosphatidylcholine (PC) biosynthesis, is crucial for various biological functions and is associated with longevity. Phosphatidylethanolamine N-methyltransferase (PEMT) is a protein that catalyzes the biosynthesis of PC, the levels of which change in various organs such as the brain and kidneys during aging. However, the role of PEMT for systemic PC supply is not fully understood. To address how PEMT affects aging-associated energy metabolism in tissues responsible for nutrient absorption, lipid storage, and energy consumption, we employed NMR-based metabolomics to study the liver, plasma, intestine (duodenum, jejunum, and ileum), brown/white adipose tissues (BAT and WAT), and skeletal muscle of young (9-10 weeks) and old (91-132 weeks) wild-type (WT) and PEMT knockout (KO) mice. We found that the effect of PEMT-knockout was tissue-specific and age-dependent. A deficiency of PEMT affected the metabolome of all tissues examined, among which the metabolome of BAT from both young and aged KO mice was dramatically changed in comparison to the WT mice, whereas the metabolome of the jejunum was only slightly affected. As for aging, the absence of PEMT increased the divergence of the metabolome during the aging of the liver, WAT, duodenum, and ileum and decreased the impact on skeletal muscle. Overall, our results suggest that PEMT plays a previously underexplored, critical role in both aging and energy metabolism.
    Keywords:  NMR; PEMT; aging; intestine; knockout; liver; metabolomics; mice; white/brown adipose tissue
    DOI:  https://doi.org/10.3390/biom12091270
  12. Adv Sci (Weinh). 2022 Sep 18. e2202855
    Emerging Implications of Phase Separation in Cancer.
    Jiang Ren, Zhenyu Zhang, Zhi Zong, Long Zhang, Fangfang Zhou.
      In eukaryotic cells, biological activities are executed in distinct cellular compartments or organelles. Canonical organelles with membrane-bound structures are well understood. Cells also inherently contain versatile membrane-less organelles (MLOs) that feature liquid or gel-like bodies. A biophysical process termed liquid-liquid phase separation (LLPS) elucidates how MLOs form through dynamic biomolecule assembly. LLPS-related molecules often have multivalency, which is essential for low-affinity inter- or intra-molecule interactions to trigger phase separation. Accumulating evidence shows that LLPS concentrates and organizes desired molecules or segregates unneeded molecules in cells. Thus, MLOs have tunable functional specificity in response to environmental stimuli and metabolic processes. Aberrant LLPS is widely associated with several hallmarks of cancer, including sustained proliferative signaling, growth suppressor evasion, cell death resistance, telomere maintenance, DNA damage repair, etc. Insights into the molecular mechanisms of LLPS provide new insights into cancer therapeutics. Here, the current understanding of the emerging concepts of LLPS and its involvement in cancer are comprehensively reviewed.
    Keywords:  biomolecular condensates; cancer; novel therapeutics; phase separation
    DOI:  https://doi.org/10.1002/advs.202202855
  13. Nat Rev Clin Oncol. 2022 Sep 23.
    Towards precision oncology with patient-derived xenografts.
    Eugenia R Zanella, Elena Grassi, Livio Trusolino.
      Under the selective pressure of therapy, tumours dynamically evolve multiple adaptive mechanisms that make static interrogation of genomic alterations insufficient to guide treatment decisions. Clinical research does not enable the assessment of how various regulatory circuits in tumours are affected by therapeutic insults over time and space. Likewise, testing different precision oncology approaches informed by composite and ever-changing molecular information is hard to achieve in patients. Therefore, preclinical models that incorporate the biology and genetics of human cancers, facilitate analyses of complex variables and enable adequate population throughput are needed to pinpoint randomly distributed response predictors. Patient-derived xenograft (PDX) models are dynamic entities in which cancer evolution can be monitored through serial propagation in mice. PDX models can also recapitulate interpatient diversity, thus enabling the identification of response biomarkers and therapeutic targets for molecularly defined tumour subgroups. In this Review, we discuss examples from the past decade of the use of PDX models for precision oncology, from translational research to drug discovery. We elaborate on how and to what extent preclinical observations in PDX models have confirmed and/or anticipated findings in patients. Finally, we illustrate emerging methodological efforts that could broaden the application of PDX models by honing their predictive accuracy or improving their versatility.
    DOI:  https://doi.org/10.1038/s41571-022-00682-6
  14. Clin Cancer Res. 2022 Sep 21. pii: CCR-22-1125. [Epub ahead of print]
    Neoadjuvant chemotherapy is associated with altered immune cell infiltration and an anti-tumorigenic microenvironment in resected pancreatic cancer.
    Andressa Dias Costa, Sara A Väyrynen, Akhil Chawla, Jinming Zhang, Juha P Väyrynen, Mai Chan Lau, Hannah L Williams, Chen Yuan, Vicente Morales-Oyarvide, Dalia Elganainy, Harshabad Singh, James M Cleary, Kimberly Perez, Kimmie Ng, William Freed-Pastor, Joseph D Mancias, Stephanie K Dougan, Jiping Wang, Douglas A Rubinson, Richard F Dunne, Margaret M Kozak, Lauren Brais, Emma Reilly, Thomas Clancy, David C Linehan, Daniel T Chang, Aram F Hezel, Albert C Koong, Andrew Aguirre, Brian M Wolpin, Jonathan A Nowak.
      PURPOSE: Neoadjuvant chemotherapy is increasingly administered to patients with resectable or borderline resectable pancreatic ductal adenocarcinoma (PDAC), yet its impact on the tumor immune microenvironment is incompletely understood.EXPERIMENTAL DESIGN: We employed quantitative, spatially-resolved multiplex immunofluorescence and digital image analysis to identify T-cell subpopulations, macrophage polarization states and myeloid cell subpopulations in a multi-institution cohort of up-front resected primary tumors (n=299) and in a comparative set of resected tumors after FOLFIRINOX-based neoadjuvant therapy (n=36) or up-front surgery (n=30). Multivariable-adjusted Cox proportional hazards models were used to evaluate associations between the immune microenvironment and patient outcomes.
    RESULTS: In the multi-institutional resection cohort, immune cells exhibited substantial heterogeneity across patient tumors and were located predominantly in stromal regions. Unsupervised clustering using immune cell densities identified four main patterns of immune cell infiltration. One pattern, seen in 20% of tumors and characterized by abundant T cells (T cell-rich) and a paucity of immunosuppressive granulocytes and macrophages, was associated with improved patient survival. Neoadjuvant chemotherapy was associated with a higher CD8:CD4 ratio, greater M1:M2-polarized macrophage ratio, and reduced CD15+ARG1+ immunosuppressive granulocyte density. Within neoadjuvant-treated tumors, 64% showed a T-cell-rich pattern with low immunosuppressive granulocytes and macrophages. M1-polarized macrophages were located closer to tumor cells after neoadjuvant chemotherapy and colocalization of M1-polarized macrophages and tumor cells was associated with greater tumor pathologic response and improved patient survival.
    CONCLUSION: Neoadjuvant chemotherapy with FOLFIRINOX shifts the PDAC immune microenvironment towards an anti-tumorigenic state associated with improved patient survival.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-1125
  15. Nature. 2022 Sep 21.
    A cellular hierarchy in melanoma uncouples growth and metastasis.
    Panagiotis Karras, Ignacio Bordeu, Joanna Pozniak, Ada Nowosad, Cecilia Pazzi, Nina Van Raemdonck, Ewout Landeloos, Yannick Van Herck, Dennis Pedri, Greet Bervoets, Samira Makhzami, Jia Hui Khoo, Benjamin Pavie, Jochen Lamote, Oskar Marin-Bejar, Michael Dewaele, Han Liang, Xingju Zhang, Yichao Hua, Jasper Wouters, Robin Browaeys, Gabriele Bergers, Yvan Saeys, Francesca Bosisio, Joost van den Oord, Diether Lambrechts, Anil K Rustgi, Oliver Bechter, Cedric Blanpain, Benjamin D Simons, Florian Rambow, Jean-Christophe Marine.
      Although melanoma is notorious for its high degree of heterogeneity and plasticity1,2, the origin and magnitude of cell-state diversity remains poorly understood. Equally, it is unclear whether growth and metastatic dissemination are supported by overlapping or distinct melanoma subpopulations. Here, by combining mouse genetics, single-cell and spatial transcriptomics, lineage tracing and quantitative modelling, we provide evidence of a hierarchical model of tumour growth that mirrors the cellular and molecular logic underlying the cell-fate specification and differentiation of the embryonic neural crest. We show that tumorigenic competence is associated with a spatially localized perivascular niche, a phenotype acquired through an intercellular communication pathway established by endothelial cells. Consistent with a model in which only a fraction of cells are fated to fuel growth, temporal single-cell tracing of a population of melanoma cells with a mesenchymal-like state revealed that these cells do not contribute to primary tumour growth but, instead, constitute a pool of metastatic initiating cells that switch cell identity while disseminating to secondary organs. Our data provide a spatially and temporally resolved map of the diversity and trajectories of melanoma cell states and suggest that the ability to support growth and metastasis are limited to distinct pools of cells. The observation that these phenotypic competencies can be dynamically acquired after exposure to specific niche signals warrant the development of therapeutic strategies that interfere with the cancer cell reprogramming activity of such microenvironmental cues.
    DOI:  https://doi.org/10.1038/s41586-022-05242-7
  16. Proc Natl Acad Sci U S A. 2022 Sep 27. 119(39): e2209823119
    In situ structural analysis reveals membrane shape transitions during autophagosome formation.
    Anna Bieber, Cristina Capitanio, Philipp S Erdmann, Fabian Fiedler, Florian Beck, Chia-Wei Lee, Delong Li, Gerhard Hummer, Brenda A Schulman, Wolfgang Baumeister, Florian Wilfling.
      Autophagosomes are unique organelles that form de novo as double-membrane vesicles engulfing cytosolic material for destruction. Their biogenesis involves membrane transformations of distinctly shaped intermediates whose ultrastructure is poorly understood. Here, we combine cell biology, correlative cryo-electron tomography (cryo-ET), and extensive data analysis to reveal the step-by-step structural progression of autophagosome biogenesis at high resolution directly within yeast cells. The analysis uncovers an unexpectedly thin intermembrane distance that is dilated at the phagophore rim. Mapping of individual autophagic structures onto a timeline based on geometric features reveals a dynamical change of membrane shape and curvature in growing phagophores. Moreover, our tomograms show the organelle interactome of growing autophagosomes, highlighting a polar organization of contact sites between the phagophore and organelles, such as the vacuole and the endoplasmic reticulum (ER). Collectively, these findings have important implications for the contribution of different membrane sources during autophagy and for the forces shaping and driving phagophores toward closure without a templating cargo.
    Keywords:  autophagosome biogenesis; autophagy; cryo-electron tomography; membrane structure; organelle contact sites
    DOI:  https://doi.org/10.1073/pnas.2209823119
  17. Biochim Biophys Acta Mol Basis Dis. 2022 Sep 20. pii: S0925-4439(22)00226-5. [Epub ahead of print] 166555
    Mechanobiology of solid tumors.
    Antonios N Gargalionis, Kostas A Papavassiliou, Athanasios G Papavassiliou.
      Mechanical features of cancer cells emerge as a distinct trait during development and progression of solid tumors. Herein, we discuss recent key findings regarding the impact of various types of mechanical stresses on cancer cell properties. Data suggest that different mechanical forces, alterations of matrix rigidity and tumor microenvironment facilitate cancer hallmarks, especially invasion and metastasis. Moreover, a subset of mechanosensory proteins are responsible for mediating mechanically induced oncogenic signaling and response to chemotherapy. Delineating cancer dynamics and decoding of respective signal transduction mechanisms will provide new therapeutic strategies against solid tumors in the future.
    Keywords:  Cancer invasion; Matrix stiffness; Mechanical stress; Mechanotransduction; Metastasis; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbadis.2022.166555
  18. Cancers (Basel). 2022 Sep 19. pii: 4526. [Epub ahead of print]14(18):
    Emerging Roles of Lipophagy in Cancer Metastasis.
    Haimeng Yin, Ying Shan, Tian Xia, Yan Ji, Ling Yuan, Yiwen You, Bo You.
      Obesity is a prominent risk factor for certain types of tumor progression. Adipocytes within tumor stroma contribute to reshaping tumor microenvironment (TME) and the metabolism and metastasis of tumors through the production of cytokines and adipokines. However, the crosstalk between adipocytes and tumor cells remains a major gap in this field. Known as a subtype of selective autophagy, lipophagy is thought to contribute to lipid metabolism by breaking down intracellular lipid droplets (LDs) and generating free fatty acids (FAs). The metastatic potential of cancer cells closely correlates with the lipid degradation mechanisms, which are required for energy generation, signal transduction, and biosynthesis of membranes. Here, we discuss the recent advance in the understanding of lipophagy with tumor lipid metabolism and review current studies on the roles of lipoghagy in the metastasis of certain human malignancies. Additionally, the novel candidate drugs targeting lipophagy are integrated for effective treatment strategies.
    Keywords:  cancer metastasis; lipid metabolism; lipophagy
    DOI:  https://doi.org/10.3390/cancers14184526
  19. Metabolites. 2022 Sep 02. pii: 831. [Epub ahead of print]12(9):
    Novel Regulators of Macropinocytosis-Dependent Growth Revealed by Informer Set Library Screening in Pancreatic Cancer Cells.
    Sang Hoon Kim, Jae Ho Song, Min Ji Kim, Mun Gu Song, Angel A Ku, Sourav Bandyopadhyay, Frank McCormick, Sung Eun Kim.
      Cancer cells utilize multiple nutrient scavenging mechanisms to support growth and survival in nutrient-poor, hypoxic tumor microenvironments. Among these mechanisms, macropinocytosis has emerged as an important pathway of extracellular nutrient acquisition in cancer cells, particularly in tumors with activated RAS signaling, such as pancreatic cancer. However, the absence of a clinically available inhibitor, as well as the gap of knowledge in macropinocytosis regulation, remain a hurdle for its use for cancer therapy. Here, we use the Informer set library to identify novel regulators of macropinocytosis-dependent growth in pancreatic cancer cells. Understanding how these regulators function will allow us to provide novel opportunities for therapeutic intervention.
    Keywords:  Informer set library screening; cancer metabolism; macropinocytosis; nutrient scavenging; pancreatic cancer
    DOI:  https://doi.org/10.3390/metabo12090831
  20. Elife. 2022 Sep 21. pii: e75227. [Epub ahead of print]11
    Proteogenomic analysis of cancer aneuploidy and normal tissues reveals divergent modes of gene regulation across cellular pathways.
    Pan Cheng, Xin Zhao, Lizabeth Katsnelson, Elaine M Camacho-Hernandez, Angela Mermerian, Joseph C Mays, Scott M Lippman, Reyna Edith Rosales-Alvarez, Raquel Moya, Jasmine Shwetar, Dominic Grun, David Fenyo, Teresa Davoli.
      How cells control gene expression is a fundamental question. The relative contribution of protein-level and RNA-level regulation to this process remains unclear. Here, we perform a proteogenomic analysis of tumors and untransformed cells containing somatic copy number alterations (SCNAs). By revealing how cells regulate RNA and protein abundances of genes with SCNAs, we provide insights into the rules of gene regulation. Protein complex genes have a strong protein-level regulation while non-complex genes have a strong RNA-level regulation. Notable exceptions are plasma membrane protein complex genes, which show a weak protein-level regulation and a stronger RNA-level regulation. Strikingly, we find a strong negative association between the degree of RNA-level and protein-level regulation across genes and cellular pathways. Moreover, genes participating in the same pathway show a similar degree of RNA- and protein-level regulation. Pathways including translation, splicing, RNA processing, and mitochondrial function show a stronger protein-level regulation while cell adhesion and migration pathways show a stronger RNA-level regulation. These results suggest that the evolution of gene regulation is shaped by functional constraints and that many cellular pathways tend to evolve one predominant mechanism of gene regulation at the protein level or at the RNA level.
    Keywords:  aneuploidy; cancer; cancer biology; computational biology; gene expression; human; protein regulation; proteogenomic; systems biology
    DOI:  https://doi.org/10.7554/eLife.75227
  21. Gels. 2022 Sep 07. pii: 567. [Epub ahead of print]8(9):
    Mechanisms of Basement Membrane Micro-Perforation during Cancer Cell Invasion into a 3D Collagen Gel.
    Shayan S Nazari, Andrew D Doyle, Kenneth M Yamada.
      Cancer invasion through basement membranes represents the initial step of tumor dissemination and metastasis. However, little is known about how human cancer cells breach basement membranes. Here, we used a three-dimensional in vitro invasion model consisting of cancer spheroids encapsulated by a basement membrane and embedded in 3D collagen gels to visualize the early events of cancer invasion by confocal microscopy and live-cell imaging. Human breast cancer cells generated large numbers of basement membrane perforations, or holes, of varying sizes that expanded over time during cell invasion. We used a wide variety of small molecule inhibitors to probe the mechanisms of basement membrane perforation and hole expansion. Protease inhibitor treatment (BB94), led to a 63% decrease in perforation size. After myosin II inhibition (blebbistatin), the basement membrane perforation area decreased by only 15%. These treatments produced correspondingly decreased cellular breaching events. Interestingly, inhibition of actin polymerization dramatically decreased basement membrane perforation by 80% and blocked invasion. Our findings suggest that human cancer cells can primarily use proteolysis and actin polymerization to perforate the BM and to expand perforations for basement membrane breaching with a relatively small contribution from myosin II contractility.
    Keywords:  3D culture; actin polymerization; cancer invasion; cell-matrix interactions; contractility; hydrogel; imaging; matrix metalloproteinases; proteases
    DOI:  https://doi.org/10.3390/gels8090567
  22. Nat Metab. 2022 Sep;4(9): 1085
    Improving the reproducibility of metabolic research.
      
    DOI:  https://doi.org/10.1038/s42255-022-00653-2
  23. JCSM Rapid Commun. 2022 Jan-Jun;5(1):5(1): 52-67
    Muscle wasting in cancer: opportunities and challenges for exercise in clinical cancer trials.
    Ciaran M Fairman, Simon Lønbro, Thomas D Cardaci, Brandon N VanderVeen, Tormod S Nilsen, Angela E Murphy.
      Background: Low muscle in cancer is associated with an increase in treatment-related toxicities and is a predictor of cancer-related and all-cause mortality. The mechanisms of cancer-related muscle loss are multifactorial, including anorexia, hypogonadism, anaemia, inflammation, malnutrition, and aberrations in skeletal muscle protein turnover and metabolism.Methods: In this narrative review, we summarise relevant literature to (i) review the factors influencing skeletal muscle mass regulation, (ii) provide an overview of how cancer/treatments negatively impact these, (iii) review factors beyond muscle signalling that can impact the ability to participate in and respond to an exercise intervention to counteract muscle loss in cancer, and (iv) provide perspectives on critical areas of future research.
    Results: Despite the well-known benefits of exercise, there remains a paucity of clinical evidence supporting the impact of exercise in cancer-related muscle loss. There are numerous challenges to reversing muscle loss with exercise in clinical cancer settings, ranging from the impact of cancer/treatments on the molecular regulation of muscle mass, to clinical challenges in responsiveness to an exercise intervention. For example, tumour-related/treatment-related factors (e.g. nausea, pain, anaemia, and neutropenia), presence of comorbidities (e.g. diabetes, arthritis, and chronic obstructive pulmonary disease), injuries, disease progression and bone metastases, concomitant medications (e.g., metformin), can negatively affect an individual's ability to exercise safely and limit subsequent adaptation.
    Conclusions: This review identifies numerous gaps and oppportunities in the area of low muscle and muscle loss in cancer. Collaborative efforts between preclinical and clinical researchers are imperative to both understanding the mechanisms of atrophy, and develop appropriate therapeutic interventions.
    Keywords:  Cachexia; Muscle loss; Resistance exercise; Sarcopenia
    DOI:  https://doi.org/10.1002/rco2.56
  24. Methods Mol Biol. 2023 ;2566 37-43
    Lysosome Imaging Based on Fluorescent Carbon Dots.
    Shuo Guo, Yuanqiang Sun, Zhaohui Li.
      Lysosomes play key roles in different cellular processes such as autophagy, phagocytosis, and apoptosis. Lysosomal dysfunction is related to many diseases. Fluorescence lysosome staining strategy is valuable for the researches on the lysosome involvement in different pathological diagnosis. Here we describe fluorescence lysosome staining methods with carbon dots for the identification of lysosomes in living and fixed cells.
    Keywords:  Carbon dots; Cell imaging; Confocal fluorescence microscopy; Lysosome
    DOI:  https://doi.org/10.1007/978-1-0716-2675-7_3
  25. Nat Cancer. 2022 Sep;3(9): 1026-1038
    Artificial intelligence in histopathology: enhancing cancer research and clinical oncology.
    Artem Shmatko, Narmin Ghaffari Laleh, Moritz Gerstung, Jakob Nikolas Kather.
      Artificial intelligence (AI) methods have multiplied our capabilities to extract quantitative information from digital histopathology images. AI is expected to reduce workload for human experts, improve the objectivity and consistency of pathology reports, and have a clinical impact by extracting hidden information from routinely available data. Here, we describe how AI can be used to predict cancer outcome, treatment response, genetic alterations and gene expression from digitized histopathology slides. We summarize the underlying technologies and emerging approaches, noting limitations, including the need for data sharing and standards. Finally, we discuss the broader implications of AI in cancer research and oncology.
    DOI:  https://doi.org/10.1038/s43018-022-00436-4
  26. Proc Natl Acad Sci U S A. 2022 Sep 27. 119(39): e2202178119
    Oxygen regulation of breathing is abolished in mitochondrial complex III-deficient arterial chemoreceptors.
    Daniel Cabello-Rivera, Patricia Ortega-Sáenz, Lin Gao, Ana M Muñoz-Cabello, Victoria Bonilla-Henao, Paul T Schumacker, José López-Barneo.
      Acute oxygen (O2) sensing is essential for adaptation of organisms to hypoxic environments or medical conditions with restricted exchange of gases in the lung. The main acute O2-sensing organ is the carotid body (CB), which contains neurosecretory chemoreceptor (glomus) cells innervated by sensory fibers whose activation by hypoxia elicits hyperventilation and increased cardiac output. Glomus cells have mitochondria with specialized metabolic and electron transport chain (ETC) properties. Reduced mitochondrial complex (MC) IV activity by hypoxia leads to production of signaling molecules (NADH and reactive O2 species) in MCI and MCIII that modulate membrane ion channel activity. We studied mice with conditional genetic ablation of MCIII that disrupts the ETC in the CB and other catecholaminergic tissues. Glomus cells survived MCIII dysfunction but showed selective abolition of responsiveness to hypoxia (increased [Ca2+] and transmitter release) with normal responses to other stimuli. Mitochondrial hypoxic NADH and reactive O2 species signals were also suppressed. MCIII-deficient mice exhibited strong inhibition of the hypoxic ventilatory response and altered acclimatization to sustained hypoxia. These data indicate that a functional ETC, with coupling between MCI and MCIV, is required for acute O2 sensing. O2 regulation of breathing results from the integrated action of mitochondrial ETC complexes in arterial chemoreceptors.
    Keywords:  acute O2 sensing; carotid body glomus cell; hypoxia; mitochondrial O2 sensing and signaling; mitochondrial complex III
    DOI:  https://doi.org/10.1073/pnas.2202178119
  27. J Am Chem Soc. 2022 Sep 19.
    Fluorescent Biosensor for Measuring Ras Activity in Living Cells.
    Ryan Weeks, Xin Zhou, Tina L Yuan, Jin Zhang.
      The small GTPase Ras is a critical regulator of cell growth and proliferation. Its activity is frequently dysregulated in cancers, prompting decades of work to pharmacologically target Ras. Understanding Ras biology and developing effective Ras therapeutics both require probing Ras activity in its native context, yet tools to measure its activities in cellulo are limited. Here, we developed a ratiometric Ras activity reporter (RasAR) that provides quantitative measurement of Ras activity in living cells with high spatiotemporal resolution. We demonstrated that RasAR can probe live-cell activities of all the primary isoforms of Ras. Given that the functional roles of different isoforms of Ras are intimately linked to their subcellular distribution and regulation, we interrogated the spatiotemporal regulation of Ras utilizing subcellularly targeted RasAR and uncovered the role of Src kinase as an upstream regulator to inhibit HRas. Furthermore, we showed that RasAR enables capture of KRasG12C inhibition dynamics in living cells upon treatment with KRasG12C covalent inhibitors, including ARS1620, Sotorasib, and Adagrasib. We found in living cells a residual Ras activity lingers for hours in the presence of these inhibitors. Together, RasAR represents a powerful molecular tool to enable live-cell interrogation of Ras activity and facilitate the development of Ras inhibitors.
    DOI:  https://doi.org/10.1021/jacs.2c05203
  28. Nat Commun. 2022 Sep 22. 13(1): 5210
    Cell Rover-a miniaturized magnetostrictive antenna for wireless operation inside living cells.
    Baju Joy, Yubin Cai, David C Bono, Deblina Sarkar.
      An intracellular antenna can open up new horizons for fundamental and applied biology. Here, we introduce the Cell Rover, a magnetostrictive antenna which can operate wirelessly inside a living cell and is compatible with 3D biological systems. It is sub-mm in size, acoustically actuated by an AC magnetic field and resonantly operated at low MHz frequencies, which is ideal for living systems. We developed an injection scheme involving non-uniform magnetic fields for intracellular injection of the Cell Rovers and demonstrated their operation in fully opaque, stage VI Xenopus oocytes, for which real-time imaging with conventional technologies is challenging. We also show that they provide a pathway for multiplexing applications to individually address multiple cells or to tune to more than one antenna within the same cell for versatile functionalities. This technology forms the foundation stone that can enable the integration of future capabilities such as smart sensing, modulation as well as energy harvesting to power in-cell nanoelectronic computing and can potentially bring the prowess of information technology inside a living cell. This could lead to unprecedented opportunities for fundamental understanding of biology as well as diagnostics and therapeutics.
    DOI:  https://doi.org/10.1038/s41467-022-32862-4
  29. Nat Commun. 2022 Sep 22. 13(1): 5550
    Protein condensation diseases: therapeutic opportunities.
    Michele Vendruscolo, Monika Fuxreiter.
      Condensed states of proteins, including liquid-like membraneless organelles and solid-like aggregates, contribute in fundamental ways to the organisation and function of the cell. Perturbations of these states can lead to a variety of diseases through mechanisms that we are now beginning to understand. We define protein condensation diseases as conditions caused by the disruption of the normal behaviour of the condensed states of proteins. We analyze the problem of the identification of targets for pharmacological interventions for these diseases and explore opportunities for the regulation of the formation and organisation of aberrant condensed states of proteins.
    DOI:  https://doi.org/10.1038/s41467-022-32940-7
  30. Front Oncol. 2022 ;12 957135
    Exercise as cancer treatment: A clinical oncology framework for exercise oncology research.
    Kerry S Courneya, Christopher M Booth.
      Exercise has been proposed as a possible cancer treatment; however, there are an infinite number of clinical oncology settings involving diverse cancer types and treatment protocols in which exercise could be tested as a cancer treatment. The primary purpose of this paper is to propose a conceptual framework to organize and guide research on exercise as a cancer treatment across distinct clinical oncology settings. A secondary purpose is to provide an overview of existing exercise research using the proposed framework. The Exercise as Cancer Treatment (EXACT) framework proposes nine distinct clinical oncology scenarios based on tumor/disease status and treatment status at the time of the proposed exercise treatment. In terms of tumor/disease status, the primary tumor has either been surgically removed (primary goal to treat micrometastases), not surgically removed (primary goal to treat the primary tumor), or metastatic disease is present (primary goal to treat metastatic disease). In terms of treatment status, the extant disease has either not been treated yet (treatment naïve), is currently being treated (active treatment), or has previously been treated. These two key clinical oncology variables-tumor/disease status and treatment status-result in nine distinct clinical oncology scenarios in which exercise could be tested as a new cancer treatment: (a) treatment naïve micrometastases, (b) actively treated micrometastases, (c) previously treated micrometastases, (d) treatment naïve primary tumors, (e) actively treated primary tumors, (f) previously treated primary tumors, (g) treatment naïve metastatic disease, (h) actively treated metastatic disease, and (i) previously treated metastatic disease. To date, most preclinical animal studies have examined the effects of exercise on treatment naïve and actively treated primary tumors. Conversely, most observational human studies have examined the associations between exercise and cancer recurrence/survival in patients actively treated or previously treated for micrometastases. Few clinical trials have been conducted in any of these scenarios. For exercise to be integrated into clinical oncology practice as a cancer treatment, it will need to demonstrate benefit in a specific clinical setting. The EXACT framework provides a simple taxonomy for systematically evaluating exercise as a potential cancer treatment across a diverse range of cancer types and treatment protocols.
    Keywords:  cancer therapy; exercise; physical activity; survival; tumor growth
    DOI:  https://doi.org/10.3389/fonc.2022.957135
  31. STAR Protoc. 2022 Sep 21. pii: S2666-1667(22)00589-5. [Epub ahead of print]3(4): 101709
    A protocol for mimicking lipid-mediated phase separation on the membrane using giant unilamellar vesicles.
    Yuanxiang Zhu, Yajie Gao, Qinmiao Sun, Dahua Chen.
      Here, we present a general protocol for mimicking lipid-mediated phase separation on the membrane using giant unilamellar vesicles (GUVs). In this protocol, we use GUVs to mimic Ago1 protein's phase separation behavior on the membrane through binding with phosphoinositides (PIPs). We provide procedures to prepare fluorescent-labeled Ago1 protein and PI(4,5)P2-containing GUVs, followed by steps to assess Ago1 protein's phase separation in 3D time-lapse images. This protocol can be applied to investigate a membrane-associated protein's behavior on the membrane. For complete details on the use and execution of this protocol, please refer to Gao et al. (2022).
    Keywords:  Cell biology; Cell membrane; Microscopy; Molecular biology; Protein biochemistry; Protein expression and purification
    DOI:  https://doi.org/10.1016/j.xpro.2022.101709
  32. J Clin Invest. 2022 Sep 20. pii: e161638. [Epub ahead of print]
    A Mitofusin 2 - Hif1α axis sets a maturation checkpoint in regenerating skeletal muscle.
    Xun Wang, Yuemeng Jia, Jiawei Zhao, Nicholas P Lesner, Cameron J Menezes, Spencer D Shelton, Siva Sai Krishna Venigalla, Jian Xu, Chunyu Cai, Prashant Mishra.
      A fundamental issue in regenerative medicine is whether there exist endogenous regulatory mechanisms that limit the speed and efficiency of the repair process. We report the existence of a maturation checkpoint during muscle regeneration which pauses myofibers at a neonatal stage. This checkpoint is regulated by the mitochondrial protein mitofusin 2 (Mfn2), whose expression is activated in response to muscle injury. Mfn2 is required for growth and maturation of regenerating myofibers; in the absence of Mfn2, new myofibers arrested at a neonatal stage, characterized by centrally nucleated myofibers and loss of H3K27me3 repressive marks at the neonatal myosin heavy chain gene. A similar arrest at the neonatal stage was observed in infantile cases of human centronuclear myopathy. Mechanistically, Mfn2 upregulation suppressed expression of Hypoxia-induced Factor 1α (Hif1α), which is induced in the setting of muscle damage. Sustained Hif1α signaling blocked maturation of new myofibers at the neonatal-to-adult fate transition, revealing the existence of a checkpoint that delays muscle regeneration. Correspondingly, inhibition of Hif1α allowed myofibers to bypass the checkpoint, thereby accelerating the repair process. We conclude that skeletal muscle contains a regenerative checkpoint which regulates the speed of myofiber maturation in response to Mitofusin 2 and Hif1α activity.
    Keywords:  Epigenetics; Mitochondria; Muscle Biology; Stem cells
    DOI:  https://doi.org/10.1172/JCI161638
  33. Sci Signal. 2022 Sep 20. 15(752): eade9136
    Telomeres to go.
    John F Foley.
      By acquiring telomeres from antigen-presenting cells, some T cells are protected from senescence.
    DOI:  https://doi.org/10.1126/scisignal.ade9136
  34. Elife. 2022 Sep 20. pii: e72498. [Epub ahead of print]11
    Empirical single-cell tracking and cell-fate simulation reveal dual roles of p53 in tumor suppression.
    Ann Rancourt, Sachiko Sato, Masahiko S Satoh.
      The tumor suppressor p53 regulates various stress responses via increasing its cellular levels. The lowest p53 levels occur in unstressed cells; however, the functions of these low levels remain unclear. To investigate the functions, we used empirical single-cell tracking of p53-expressing (Control) cells and cells in which p53 expression was silenced by RNA interference (p53 RNAi). Here we show that p53 RNAi cells underwent more frequent cell death and cell fusion, which further induced multipolar cell division to generate aneuploid progeny. Those results suggest that the low levels of p53 in unstressed cells indeed have a role in suppressing the induction of cell death and the formation of aneuploid cells. We further investigated the impact of p53 silencing by developing an algorithm to simulate the fates of individual cells. Simulation of the fate of aneuploid cells revealed that these cells could propagate to create an aneuploid cell population. In addition, the simulation also revealed that more frequent induction of cell death in p53 RNAi cells under unstressed conditions conferred a disadvantage in terms of population expansion compared with Control cells, resulting in faster expansion of Control cells compared with p53 RNAi cells, leading to Control cells predominating in mixed cell populations. In contrast, the expansion of Control cells, but not p53 RNAi cells, was suppressed when the damage response was induced, allowing p53 RNAi cells to expand their population compared with the Control cells. These results suggest that, although p53 could suppress the formation of aneuploid cells, which could have a role in tumorigenesis, it could also allow the expansion of cells lacking p53 expression when the damage response is induced. p53 may thus play a role in both the suppression and the promotion of malignant cell formation during tumorigenesis.
    Keywords:  computational biology; human; systems biology
    DOI:  https://doi.org/10.7554/eLife.72498
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