bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2022‒01‒16
forty-one papers selected by
Kıvanç Görgülü
Technical University of Munich
  1. Restriction of extracellular lipids renders pancreatic cancer dependent on autophagy.
  2. Chemotherapy-induced infiltration of neutrophils promotes pancreatic cancer metastasis via Gas6/AXL signalling axis.
  3. A GATA4-regulated secretory program suppresses tumors through recruitment of cytotoxic CD8 T cells.
  4. Towards targeting of shared mechanisms of cancer metastasis and therapy resistance.
  5. Aging Aggravates Cachexia in Tumor-Bearing Mice.
  6. Physical exercise at the crossroad between muscle wasting and the immune system: implications for lung cancer cachexia.
  7. Genetic Mutations of Pancreatic Cancer and Genetically Engineered Mouse Models.
  8. Association between Platelet Count with 1-year Survival in Patients with Cancer Cachexia.
  9. Extracellular Vesicles from Pancreatic Cancer Stem Cells Lead an Intratumor Communication Network (EVNet) to fuel tumour progression.
  10. Progranulin mediates immune evasion of pancreatic ductal adenocarcinoma through regulation of MHCI expression.
  11. Mosaic dysfunction of mitophagy in mitochondrial muscle disease.
  12. Aberrant lipid metabolism in cancer cells and tumor microenvironment: the player rather than bystander in cancer progression and metastasis.
  13. Targeting the undruggable oncogenic KRAS: the dawn of hope.
  14. CDK4 and CDK6 kinases: From basic science to cancer therapy.
  15. Systems-level analysis of insulin action in mouse strains provides insight into tissue- and pathway-specific interactions that drive insulin resistance.
  16. Mechanism of Atg9 recruitment by Atg11 in the cytoplasm-to-vacuole targeting pathway.
  17. Programmed cell death 1 ligand 1 signals in cancer cells.
  18. Atlas of exercise metabolism reveals time-dependent signatures of metabolic homeostasis.
  19. Age influences on the molecular presentation of tumours.
  20. Molecular Mechanisms and Regulation of Mammalian Mitophagy.
  21. Pancreatic stromal Gremlin 1 expression during pancreatic tumorigenesis.
  22. Active RB causes visible changes in nuclear organization.
  23. The role of m6A RNA methylation in cancer metabolism.
  24. C/EBPβ promotes the expression of atrophy-inducing factors by tumours and is a central regulator of cancer cachexia.
  25. CellRank for directed single-cell fate mapping.
  26. The complex interplay between autophagy and cell death pathways.
  27. Targeting Cellular Senescence with Senotherapeutics: Senolytics and Senomorphics.
  28. An inducible p21-Cre mouse model to monitor and manipulate p21-highly-expressing senescent cells in vivo.
  29. Hypophosphorylated pRb knock-in mice exhibit hallmarks of aging and vitamin C-preventable diabetes.
  30. GAK and PRKCD kinases regulate basal mitophagy.
  31. Cytosolic Quality Control of Mitochondrial Protein Precursors-The Early Stages of the Organelle Biogenesis.
  32. Functional CDKN2A assay identifies frequent deleterious alleles misclassified as variants of uncertain significance.
  33. Genome-wide screens identify specific drivers of mutant hTERT promoters.
  34. Lipidomic profiling of human serum enables detection of pancreatic cancer.
  35. Reprogramming of nucleotide metabolism by interferon confers dependence on the replication stress response pathway in pancreatic cancer cells.
  36. The Impact of Exercise on Telomere Length, DNA Methylation and Metabolic Footprints.
  37. Microfluidic Platforms for High-Throughput Pancreatic Ductal Adenocarcinoma Organoid Culture and Drug Screening.
  38. Rethinking the TNM Classification Regarding Direct Lymph Node Invasion in Pancreatic Ductal Adenocarcinoma.
  39. Cell2location maps fine-grained cell types in spatial transcriptomics.
  40. The effect of the low stromal ratio induced by neoadjuvant chemotherapy on recurrence patterns in borderline resectable pancreatic ductal adenocarcinoma.
  41. Preclinical cancer research suffers another reproducibility blow.
  1. J Exp Clin Cancer Res. 2022 Jan 08. 41(1): 16
    Restriction of extracellular lipids renders pancreatic cancer dependent on autophagy.
    Maria Saliakoura, Matteo Rossi Sebastiano, Ioanna Nikdima, Chiara Pozzato, Georgia Konstantinidou.
      BACKGROUND: KRAS is the predominant oncogene mutated in pancreatic ductal adenocarcinoma (PDAC), the fourth cause of cancer-related deaths worldwide. Mutant KRAS-driven tumors are metabolically programmed to support their growth and survival, which can be used to identify metabolic vulnerabilities. In the present study, we aimed to understand the role of extracellularly derived fatty acids in KRAS-driven pancreatic cancer.METHODS: To assess the dependence of PDAC cells on extracellular fatty acids we employed delipidated serum or RNAi-mediated suppression of ACSL3 (to inhibit the activation and cellular retention of extracellular fatty acids) followed by cell proliferation assays, qPCR, apoptosis assays, immunoblots and fluorescence microscopy experiments. To assess autophagy in vivo, we employed the KrasG12D/+;p53flox/flox;Pdx1-CreERT2 (KPC) mice crossed with Acsl3 knockout mice, and to assess the efficacy of the combination therapy of ACSL3 and autophagy inhibition we used xenografted human cancer cell-derived tumors in immunocompromised mice.
    RESULTS: Here we show that depletion of extracellularly derived lipids either by serum lipid restriction or suppression of ACSL3, triggers autophagy, a process that protects PDAC cells from the reduction of bioenergetic intermediates. Combined extracellular lipid deprivation and autophagy inhibition exhibits anti-proliferative and pro-apoptotic effects against PDAC cell lines in vitro and promotes suppression of xenografted human pancreatic cancer cell-derived tumors in mice. Therefore, we propose lipid deprivation and autophagy blockade as a potential co-targeting strategy for PDAC treatment.
    CONCLUSIONS: Our work unravels a central role of extracellular lipid supply in ensuring fatty acid provision in cancer cells, unmasking a previously unappreciated metabolic vulnerability of PDAC cells.
    Keywords:  Combination therapy; Extracellular lipids; Lipid metabolism; Pancreatic cancer; Tumor metabolic vulnerabilities
    DOI:  https://doi.org/10.1186/s13046-021-02231-y
  2. Gut. 2022 Jan 12. pii: gutjnl-2021-325272. [Epub ahead of print]
    Chemotherapy-induced infiltration of neutrophils promotes pancreatic cancer metastasis via Gas6/AXL signalling axis.
    Gaia Bellomo, Carolyn Rainer, Valeria Quaranta, Yuliana Astuti, Meirion Raymant, Elzbieta Boyd, Ruth Stafferton, Fiona Campbell, Paula Ghaneh, Christopher M Halloran, Dean E Hammond, Jennifer P Morton, Daniel Palmer, Dale Vimalachandran, Robert Jones, Ainhoa Mielgo, Michael C Schmid.
      OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease and cytotoxic chemotherapy is the standard of care treatment for patients with advanced disease. Here, we investigate how the microenvironment in PDAC liver metastases reacts to chemotherapy and its role in metastatic disease progression post-treatment, an area which is poorly understood.DESIGN: The impact of chemotherapy on metastatic disease progression and immune cell infiltrates was characterised using flow and mass cytometry combined with transcriptional and histopathological analysis in experimental PDAC liver metastases mouse models. Findings were validated in patient derived liver metastases and in an autochthonous PDAC mouse model. Human and murine primary cell cocultures and ex vivo patient-derived liver explants were deployed to gain mechanistical insights on whether and how chemotherapy affects the metastatic tumour microenvironment.
    RESULTS: We show that in vivo, chemotherapy induces an initial infiltration of proinflammatory macrophages into the liver and activates cytotoxic T cells, leading only to a temporary restraining of metastatic disease progression. However, after stopping treatment, neutrophils are recruited to the metastatic liver via CXCL1 and 2 secretion by metastatic tumour cells. These neutrophils express growth arrest specific 6 (Gas6) which leads to AXL receptor activation on tumour cells enabling their regrowth. Disruption of neutrophil infiltration or inhibition of the Gas6/AXL signalling axis in combination with chemotherapy inhibits metastatic growth. Chemotherapy increases Gas6 expression in circulating neutrophils from patients with metastatic pancreatic cancer and recombinant Gas6 is sufficient to promote tumour cell proliferation ex vivo, in patient-derived metastatic liver explants.
    CONCLUSION: Combining chemotherapy with Gas6/AXL or neutrophil targeted therapy could provide a therapeutic benefit for patients with metastatic pancreatic cancer.
    Keywords:  immune response; liver metastases; macrophages; pancreatic cancer
    DOI:  https://doi.org/10.1136/gutjnl-2021-325272
  3. Nat Commun. 2022 Jan 11. 13(1): 256
    A GATA4-regulated secretory program suppresses tumors through recruitment of cytotoxic CD8 T cells.
    Rupesh S Patel, Rodrigo Romero, Emma V Watson, Anthony C Liang, Megan Burger, Peter M K Westcott, Kim L Mercer, Roderick T Bronson, Eric C Wooten, Arjun Bhutkar, Tyler Jacks, Stephen J Elledge.
      The GATA4 transcription factor acts as a master regulator of development of multiple tissues. GATA4 also acts in a distinct capacity to control a stress-inducible pro-inflammatory secretory program that is associated with senescence, a potent tumor suppression mechanism, but also operates in non-senescent contexts such as tumorigenesis. This secretory pathway is composed of chemokines, cytokines, growth factors, and proteases. Since GATA4 is deleted or epigenetically silenced in cancer, here we examine the role of GATA4 in tumorigenesis in mouse models through both loss-of-function and overexpression experiments. We find that GATA4 promotes non-cell autonomous tumor suppression in multiple model systems. Mechanistically, we show that Gata4-dependent tumor suppression requires cytotoxic CD8 T cells and partially requires the secreted chemokine CCL2. Analysis of transcriptome data in human tumors reveals reduced lymphocyte infiltration in GATA4-deficient tumors, consistent with our murine data. Notably, activation of the GATA4-dependent secretory program combined with an anti-PD-1 antibody robustly abrogates tumor growth in vivo.
    DOI:  https://doi.org/10.1038/s41467-021-27731-5
  4. Nat Rev Cancer. 2022 Jan 10.
    Towards targeting of shared mechanisms of cancer metastasis and therapy resistance.
    Felix Weiss, Douglas Lauffenburger, Peter Friedl.
      Resistance to therapeutic treatment and metastatic progression jointly determine a fatal outcome of cancer. Cancer metastasis and therapeutic resistance are traditionally studied as separate fields using non-overlapping strategies. However, emerging evidence, including from in vivo imaging and in vitro organotypic culture, now suggests that both programmes cooperate and reinforce each other in the invasion niche and persist upon metastatic evasion. As a consequence, cancer cell subpopulations exhibiting metastatic invasion undergo multistep reprogramming that - beyond migration signalling - supports repair programmes, anti-apoptosis processes, metabolic adaptation, stemness and survival. Shared metastasis and therapy resistance signalling are mediated by multiple mechanisms, such as engagement of integrins and other context receptors, cell-cell communication, stress responses and metabolic reprogramming, which cooperate with effects elicited by autocrine and paracrine chemokine and growth factor cues present in the activated tumour microenvironment. These signals empower metastatic cells to cope with therapeutic assault and survive. Identifying nodes shared in metastasis and therapy resistance signalling networks should offer new opportunities to improve anticancer therapy beyond current strategies, to eliminate both nodular lesions and cells in metastatic transit.
    DOI:  https://doi.org/10.1038/s41568-021-00427-0
  5. Cancers (Basel). 2021 Dec 24. pii: 90. [Epub ahead of print]14(1):
    Aging Aggravates Cachexia in Tumor-Bearing Mice.
    Julia Geppert, Alina A Walth, Raúl Terrón Expósito, Doris Kaltenecker, Pauline Morigny, Juliano Machado, Maike Becker, Estefania Simoes, Joanna D C C Lima, Carolin Daniel, Mauricio Berriel Diaz, Stephan Herzig, Marilia Seelaender, Maria Rohm.
      BACKGROUND: Cancer is primarily a disease of high age in humans, yet most mouse studies on cancer cachexia are conducted using young adolescent mice. Given that metabolism and muscle function change with age, we hypothesized that aging may affect cachexia progression in mouse models.METHODS: We compare tumor and cachexia development in young and old mice of three different strains (C57BL/6J, C57BL/6N, BALB/c) and with two different tumor cell lines (Lewis Lung Cancer, Colon26). Tumor size, body and organ weights, fiber cross-sectional area, circulating cachexia biomarkers, and molecular markers of muscle atrophy and adipose tissue wasting are shown. We correlate inflammatory markers and body weight dependent on age in patients with cancer.
    RESULTS: We note fundamental differences between mouse strains. Aging aggravates weight loss in LLC-injected C57BL/6J mice, drives it in C57BL/6N mice, and does not influence weight loss in C26-injected BALB/c mice. Glucose tolerance is unchanged in cachectic young and old mice. The stress marker GDF15 is elevated in cachectic BALB/c mice independent of age and increased in old C57BL/6N and J mice. Inflammatory markers correlate significantly with weight loss only in young mice and patients.
    CONCLUSIONS: Aging affects cachexia development and progression in mice in a strain-dependent manner and influences the inflammatory profile in both mice and patients. Age is an important factor to consider for future cachexia studies.
    Keywords:  aging; cachexia; cancer; mouse models
    DOI:  https://doi.org/10.3390/cancers14010090
  6. J Cachexia Sarcopenia Muscle. 2022 Jan 10.
    Physical exercise at the crossroad between muscle wasting and the immune system: implications for lung cancer cachexia.
    Francesco Cortiula, Lizza E L Hendriks, Wouter R P H van de Worp, Annemie M W J Schols, Rianne D W Vaes, Ramon C J Langen, Dirk De Ruysscher.
      Cachexia is a syndrome characterized by involuntary weight loss and wasting of skeletal muscle mass. It is associated with worse overall survival and quality of life. The cancer-induced systemic inflammation and the consequent host derived catabolic stimuli, trigger cachexia by inhibiting muscle protein synthesis and enhancing muscle catabolism. The muscle itself may further promote chronic inflammation, introducing a vicious catabolic circle. Nutritional support alone plays a limited role in the treatment of cancer cachexia and should be combined with other interventions. Physical exercise lowers systemic inflammation and promotes muscle anabolism. It also attenuates the age-related physical decline in elderly and it might counteract the muscle wasting induced by the cancer cachexia syndrome. This review describes how cancer-induced systemic inflammation promotes muscle wasting and whether physical exercise may represent a suitable treatment for cancer-induced cachexia, particularly in patients with non-small cell lung cancer. We summarized pre-clinical and clinical studies investigating whether physical exercise would improve muscle performance and whether this improvement would translate in a clinically meaningful benefit for patients with cancer, in terms of survival and quality of life. Moreover, this review describes the results of studies investigating the interplay between physical exercise and the immune system, including the role of the intestinal microbiota.
    Keywords:  Cachexia; Gut microbiota; Immune system; Physical exercise; Systemic inflammation
    DOI:  https://doi.org/10.1002/jcsm.12900
  7. Cancers (Basel). 2021 Dec 24. pii: 71. [Epub ahead of print]14(1):
    Genetic Mutations of Pancreatic Cancer and Genetically Engineered Mouse Models.
    Yuriko Saiki, Can Jiang, Masaki Ohmuraya, Toru Furukawa.
      Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy, and the seventh leading cause of cancer-related deaths worldwide. An improved understanding of tumor biology and novel therapeutic discoveries are needed to improve overall survival. Recent multi-gene analysis approaches such as next-generation sequencing have provided useful information on the molecular characterization of pancreatic tumors. Different types of pancreatic cancer and precursor lesions are characterized by specific molecular alterations. Genetically engineered mouse models (GEMMs) of PDAC are useful to understand the roles of altered genes. Most GEMMs are driven by oncogenic Kras, and can recapitulate the histological and molecular hallmarks of human PDAC and comparable precursor lesions. Advanced GEMMs permit the temporally and spatially controlled manipulation of multiple target genes using a dual-recombinase system or CRISPR/Cas9 gene editing. GEMMs that express fluorescent proteins allow cell lineage tracing to follow tumor growth and metastasis to understand the contribution of different cell types in cancer progression. GEMMs are widely used for therapeutic optimization. In this review, we summarize the main molecular alterations found in pancreatic neoplasms, developed GEMMs, and the contribution of GEMMs to the current understanding of PDAC pathobiology. Furthermore, we attempted to modify the categorization of altered driver genes according to the most updated findings.
    Keywords:  GEMM; KRAS; PDAC
    DOI:  https://doi.org/10.3390/cancers14010071
  8. J Cancer. 2021 ;12(24): 7436-7444
    Association between Platelet Count with 1-year Survival in Patients with Cancer Cachexia.
    Yuying Liu, Yizhong Ge, Qinqin Li, Guotian Ruan, Qi Zhang, Xi Zhang, Meng Tang, Mengmeng Song, Xiaowei Zhang, Xiangrui Li, Kangping Zhang, Ming Yang, Chunlei Hu, Tong Liu, Hailun Xie, Yongbing Chen, Kaiying Yu, Minghua Cong, Wei Li, Zhengping Wang, Hanping Shi.
      Background: Changes in platelet count (PLT) are strongly associated with patient survival and may be clinically indicative of certain underlying diseases. However, there were few studies on the prognosis of patients with cancer cachexia. Objective: The purpose of this study was to investigate the relationship between PLT and 1-year survival in patients with cancer cachexia. Methods: We performed a nested case-control study of data from a multicenter clinical study of cancer. There were 252 patients with cancer cachexia whose survival time was less than or equal to 1 year and 252 patients with cancer cachexia whose survival time was more than 1 year meeting the inclusion criteria. The mortality risk and the adjusted risk were estimated by logistic regression and displayed as odds ratios (ORs) and 95% confidence intervals (95% CIs). Results: PLT was negatively correlated with 1-year overall survival (OS) of patients with cancer cachexia (increased per standard deviation (SD): OR = 1.29; 95% CI: 1.05-1.60; P = 0.018). The higher the PLT, the lower the OS of patients. When classified by dichotomy (D1 < 296×109/L, D2 ≥ 296×109/L), OS of patients in the D2 group was worse (OR = 2.18; 95% CI: 1.38-3.47; P = 0.001). When classified by quartile (Q1- Q3 < 305×109/L, Q4 ≥ 305×109/L), OS of patients in the Q4 group was poorer (OR = 1.82; 95% CI: 1.14-2.94; P = 0.013). In addition, patients with a low PLT (< 296×109/L) and either a high total bilirubin (TBIL) (≥ 17.1 µmol/L) or a smoking history had poor 1-year survival. Based on our primary cohort study, we conducted a survival analysis of 3130 patients with cancer cachexia and found that OS was better in patients with low PLT (< 296×109/L). Conclusion: PLT was negatively correlated with 1-year overall survival of patients with cancer cachexia.
    Keywords:  cancer cachexia; nested case-control study; platelet count; survival
    DOI:  https://doi.org/10.7150/jca.62788
  9. Gut. 2022 Jan 10. pii: gutjnl-2021-324994. [Epub ahead of print]
    Extracellular Vesicles from Pancreatic Cancer Stem Cells Lead an Intratumor Communication Network (EVNet) to fuel tumour progression.
    Carolina F Ruivo, Nuno Bastos, Barbara Adem, Ines Batista, Cecilia Duraes, Carlos A Melo, Stephanie A Castaldo, Francisco Campos-Laborie, Pedro Moutinho-Ribeiro, Barbara Morão, Ana Costa-Pinto, Soraia Silva, Hugo Osorio, Sergio Ciordia, Jose Luis Costa, David Goodrich, Bruno Cavadas, Luisa Pereira, Tony Kouzarides, Guilherme Macedo, Rui Maio, Fatima Carneiro, Marília Cravo, Raghu Kalluri, Jose Carlos Machado, Sonia A Melo.
      OBJECTIVE: Intratumor heterogeneity drives cancer progression and therapy resistance. However, it has yet to be determined whether and how subpopulations of cancer cells interact and how this interaction affects the tumour.DESIGN: We have studied the spontaneous flow of extracellular vesicles (EVs) between subpopulations of cancer cells: cancer stem cells (CSC) and non-stem cancer cells (NSCC). To determine the biological significance of the most frequent communication route, we used pancreatic ductal adenocarcinoma (PDAC) orthotopic models, patient-derived xenografts (PDXs) and genetically engineered mouse models (GEMMs).
    RESULTS: We demonstrate that PDAC tumours establish an organised communication network between subpopulations of cancer cells using EVs called the EVNet). The EVNet is plastic and reshapes in response to its environment. Communication within the EVNet occurs preferentially from CSC to NSCC. Inhibition of this communication route by impairing Rab27a function in orthotopic xenographs, GEMMs and PDXs is sufficient to hamper tumour growth and phenocopies the inhibition of communication in the whole tumour. Mechanistically, we provide evidence that CSC EVs use agrin protein to promote Yes1 associated transcriptional regulator (YAP) activation via LDL receptor related protein 4 (LRP-4). Ex vivo treatment of PDXs with antiagrin significantly impairs proliferation and decreases the levels of activated YAP.Patients with high levels of agrin and low inactive YAP show worse disease-free survival. In addition, patients with a higher number of circulating agrin+ EVs show a significant increased risk of disease progression.
    CONCLUSION: PDAC tumours establish a cooperation network mediated by EVs that is led by CSC and agrin, which allows tumours to adapt and thrive. Targeting agrin could make targeted therapy possible for patients with PDAC and has a significant impact on CSC that feeds the tumour and is at the centre of therapy resistance.
    Keywords:  carcinogenesis; cell biology; molecular carcinogenesis; pancreatic cancer
    DOI:  https://doi.org/10.1136/gutjnl-2021-324994
  10. Nat Commun. 2022 Jan 10. 13(1): 156
    Progranulin mediates immune evasion of pancreatic ductal adenocarcinoma through regulation of MHCI expression.
    Phyllis F Cheung, JiaJin Yang, Rui Fang, Arianna Borgers, Kirsten Krengel, Anne Stoffel, Kristina Althoff, Chi Wai Yip, Elaine H L Siu, Linda W C Ng, Karl S Lang, Lamin B Cham, Daniel R Engel, Camille Soun, Igor Cima, Björn Scheffler, Jana K Striefler, Marianne Sinn, Marcus Bahra, Uwe Pelzer, Helmut Oettle, Peter Markus, Esther M M Smeets, Erik H J G Aarntzen, Konstantinos Savvatakis, Sven-Thorsten Liffers, Smiths S Lueong, Christian Neander, Anna Bazarna, Xin Zhang, Annette Paschen, Howard C Crawford, Anthony W H Chan, Siu Tim Cheung, Jens T Siveke.
      Immune evasion is indispensable for cancer initiation and progression, although its underlying mechanisms in pancreatic ductal adenocarcinoma (PDAC) are not fully known. Here, we characterize the function of tumor-derived PGRN in promoting immune evasion in primary PDAC. Tumor- but not macrophage-derived PGRN is associated with poor overall survival in PDAC. Multiplex immunohistochemistry shows low MHC class I (MHCI) expression and lack of CD8+ T cell infiltration in PGRN-high tumors. Inhibition of PGRN abrogates autophagy-dependent MHCI degradation and restores MHCI expression on PDAC cells. Antibody-based blockade of PGRN in a PDAC mouse model remarkably decelerates tumor initiation and progression. Notably, tumors expressing LCMV-gp33 as a model antigen are sensitized to gp33-TCR transgenic T cell-mediated cytotoxicity upon PGRN blockade. Overall, our study shows a crucial function of tumor-derived PGRN in regulating immunogenicity of primary PDAC.
    DOI:  https://doi.org/10.1038/s41467-021-27088-9
  11. Cell Metab. 2022 Jan 07. pii: S1550-4131(21)00636-7. [Epub ahead of print]
    Mosaic dysfunction of mitophagy in mitochondrial muscle disease.
    Takayuki Mito, Amy E Vincent, Julie Faitg, Robert W Taylor, Nahid A Khan, Thomas G McWilliams, Anu Suomalainen.
      Mitophagy is a quality control mechanism that eliminates damaged mitochondria, yet its significance in mammalian pathophysiology and aging has remained unclear. Here, we report that mitophagy contributes to mitochondrial dysfunction in skeletal muscle of aged mice and human patients. The early disease stage is characterized by muscle fibers with central nuclei, with enhanced mitophagy around these nuclei. However, progressive mitochondrial dysfunction halts mitophagy and disrupts lysosomal homeostasis. Interestingly, activated or halted mitophagy occur in a mosaic manner even in adjacent muscle fibers, indicating cell-autonomous regulation. Rapamycin restores mitochondrial turnover, indicating mTOR-dependence of mitochondrial recycling in advanced disease stage. Our evidence suggests that (1) mitophagy is a hallmark of age-related mitochondrial pathology in mammalian muscle, (2) mosaic halting of mitophagy is a mechanism explaining mosaic respiratory chain deficiency and accumulation of pathogenic mtDNA variants in adult-onset mitochondrial diseases and normal aging, and (3) augmenting mitophagy is a promising therapeutic approach for muscle mitochondrial dysfunction.
    Keywords:  SBFSEM; centrally nucleated fibers; lysosome; mito-QC; mitochondrial disease; mitochondrial myopathy; mitophagy; patient; ragged-red fibers
    DOI:  https://doi.org/10.1016/j.cmet.2021.12.017
  12. J Cancer. 2021 ;12(24): 7498-7506
    Aberrant lipid metabolism in cancer cells and tumor microenvironment: the player rather than bystander in cancer progression and metastasis.
    Xiujing Yu, Shuyi Mi, Jun Ye, Guochun Lou.
      As the primary cause of cancer-induced fatality and morbidity, cancer metastasis has been a hard nut to crack. Existing studies indicate that lipid metabolism reprogramming occurring in cancer cells and surrounding cells in TME also endows the aggressive and spreading properties with malignant cells. In this review we describe the lipid metabolic reprogramming of cancer cells at different steps along the metastatic process, we also summarize the altered lipid metabolism of non-cancer cells in TME during tumor metastasis. Additionally, we reveal both intrinsic and extrinsic factors which influence the cellular lipid metabolism reprogramming.
    Keywords:  cancer metastasis; extrinsic factors; intrinsic factors; lipid metabolism remodeling; tumor microenvironment
    DOI:  https://doi.org/10.7150/jca.64833
  13. JCI Insight. 2022 Jan 11. pii: e153688. [Epub ahead of print]7(1):
    Targeting the undruggable oncogenic KRAS: the dawn of hope.
    Hande Asimgil, Utku Ertetik, Nedim Can Çevik, Menar Ekizce, Alper Doğruöz, Muazzez Gökalp, Elif Arık-Sever, Rouzanna Istvanffy, Helmut Friess, Güralp Onur Ceyhan, Ihsan Ekin Demir.
      KRAS mutations are the drivers of various cancers, including non-small cell lung cancer, colon cancer, and pancreatic cancer. Over the last 30 years, immense efforts have been made to inhibit KRAS mutants and oncogenic KRAS signaling using inhibitors. Recently, specific targeting of KRAS mutants with small molecules revived the hopes for successful therapies for lung, pancreatic, and colorectal cancer patients. Moreover, advances in gene editing, protein engineering, and drug delivery formulations have revolutionized cancer therapy regimens. New therapies aim to improve immune surveillance and enhance antitumor immunity by precisely targeting cancer cells harboring oncogenic KRAS. Here, we review recent KRAS-targeting strategies, their therapeutic potential, and remaining challenges to overcome. We also highlight the potential synergistic effects of various combinatorial therapies in preclinical and clinical trials.
    DOI:  https://doi.org/10.1172/jci.insight.153688
  14. Science. 2022 Jan 14. 375(6577): eabc1495
    CDK4 and CDK6 kinases: From basic science to cancer therapy.
    Anne Fassl, Yan Geng, Piotr Sicinski.
      [Figure: see text].
    DOI:  https://doi.org/10.1126/science.abc1495
  15. Cell Metab. 2022 Jan 03. pii: S1550-4131(21)00632-X. [Epub ahead of print]
    Systems-level analysis of insulin action in mouse strains provides insight into tissue- and pathway-specific interactions that drive insulin resistance.
    Marin E Nelson, Søren Madsen, Kristen C Cooke, Andreas M Fritzen, Ida H Thorius, Stewart W C Masson, Luke Carroll, Fiona C Weiss, Marcus M Seldin, Meg Potter, Samantha L Hocking, Daniel J Fazakerley, Amanda E Brandon, Senthil Thillainadesan, Alistair M Senior, Gregory J Cooney, Jacqueline Stöckli, David E James.
      Skeletal muscle and adipose tissue insulin resistance are major drivers of metabolic disease. To uncover pathways involved in insulin resistance, specifically in these tissues, we leveraged the metabolic diversity of different dietary exposures and discrete inbred mouse strains. This revealed that muscle insulin resistance was driven by gene-by-environment interactions and was strongly correlated with hyperinsulinemia and decreased levels of ten key glycolytic enzymes. Remarkably, there was no relationship between muscle and adipose tissue insulin action. Adipocyte size profoundly varied across strains and diets, and this was strongly correlated with adipose tissue insulin resistance. The A/J strain, in particular, exhibited marked adipocyte insulin resistance and hypertrophy despite robust muscle insulin responsiveness, challenging the role of adipocyte hypertrophy per se in systemic insulin resistance. These data demonstrate that muscle and adipose tissue insulin resistance can occur independently and underscore the need for tissue-specific interrogation to understand metabolic disease.
    Keywords:  GxE; Western diet; adipose; glucose uptake; glycolysis; insulin resistance; metabolism; obesity; proteomics; skeletal muscle
    DOI:  https://doi.org/10.1016/j.cmet.2021.12.013
  16. J Biol Chem. 2022 Jan 07. pii: S0021-9258(22)00013-8. [Epub ahead of print] 101573
    Mechanism of Atg9 recruitment by Atg11 in the cytoplasm-to-vacuole targeting pathway.
    Nicolas Coudevylle, Bartłomiej Banaś, Verena Baumann, Martina Schuschnig, Anna Zawadzka-Kazimierczuk, Wiktor Koźmiński, Sascha Martens.
      Autophagy is a lysosomal degradation pathway for the removal of damaged and superfluous cytoplasmic material. This is achieved by the sequestration of this cargo material within double membrane vesicles termed autophagosomes. Autophagosome formation is mediated by the conserved autophagy machinery. In selective autophagy this machinery including the transmembrane protein Atg9 is recruited to specific cargo material via cargo receptors and the Atg11/FIP200 scaffold protein. The molecular details of the interaction between Atg11 and Atg9 are unclear and it is still unknown how the recruitment of Atg9 is regulated. Here we employ NMR spectroscopy of the N-terminal disordered domain of Atg9 (Atg9-NTD) to map its interaction with Atg11 revealing that it involves two short peptides both containing a PLF motif. We show that the Atg9-NTD binds to Atg11 with an affinity of about 1 micromolar and that both PLF motifs contribute to the interaction. Mutation of the PLF motifs abolishes the interaction of Atg9-NTD with Atg11, reduces the recruitment of Atg9 to the precursor aminopeptidase 1 (prApe1) cargo and blocks prApe1 transport into the vacuole by the selective autophagy-like cytoplasm-to-vacuole (Cvt) targeting pathway while not affecting bulk autophagy. Our results provide mechanistic insights into the interaction of the Atg11 scaffold with the Atg9 transmembrane protein in selective autophagy and suggest a model where only clustered Atg11 when bound to the prApe1 cargo is able to efficiently recruit Atg9 vesicles.
    Keywords:  Autophagy; Intrinsically disordered proteins; Isothermal titration calorimetry; Nuclear magnetic resonance; yeast metabolism
    DOI:  https://doi.org/10.1016/j.jbc.2022.101573
  17. Nat Rev Cancer. 2022 Jan 14.
    Programmed cell death 1 ligand 1 signals in cancer cells.
    Anand V R Kornepati, Ratna K Vadlamudi, Tyler J Curiel.
      The paradigm of surface-expressed PDL1 signalling to immune cell PD1 to inhibit antitumour immunity has helped to develop effective and revolutionary immunotherapies using antibodies blocking these cell-extrinsic interactions. The recent discovery of cancer cell-intrinsic PDL1 signals has broadened understanding of pathologic tumour PDL1 signal consequences that now includes control of tumour growth and survival pathways, stemness, immune effects, DNA damage responses and gene expression regulation. Many such effects are PD1-independent. These insights demonstrate that the prevailing cell-extrinsic PDL1 signalling paradigm is useful, but incomplete in important respects. This Perspective discusses historical and recent advances in understanding cancer cell-intrinsic PDL1 signals, mechanisms for signal controls and important immunopathologic consequences including resistance to cytotoxic agents, targeted small molecules and immunotherapies. Cancer cell-intrinsic PDL1 signals present novel drug discovery targets and also have potential as reliable treatment response biomarkers. Cancer cell-intrinsic PD1 signals and cell-intrinsic PDL1 signals in non-cancer cells are discussed briefly, as are PDL1 signals from soluble and vesicle-bound PDL1 and PDL1 isoforms. We conclude with suggestions for addressing the most pressing challenges and opportunities in this rapidly developing field.
    DOI:  https://doi.org/10.1038/s41568-021-00431-4
  18. Cell Metab. 2022 Jan 10. pii: S1550-4131(21)00635-5. [Epub ahead of print]
    Atlas of exercise metabolism reveals time-dependent signatures of metabolic homeostasis.
    Shogo Sato, Kenneth A Dyar, Jonas T Treebak, Sara L Jepsen, Amy M Ehrlich, Stephen P Ashcroft, Kajetan Trost, Thomas Kunzke, Verena M Prade, Lewin Small, Astrid Linde Basse, Milena Schönke, Siwei Chen, Muntaha Samad, Pierre Baldi, Romain Barrès, Axel Walch, Thomas Moritz, Jens J Holst, Dominik Lutter, Juleen R Zierath, Paolo Sassone-Corsi.
      Tissue sensitivity and response to exercise vary according to the time of day and alignment of circadian clocks, but the optimal exercise time to elicit a desired metabolic outcome is not fully defined. To understand how tissues independently and collectively respond to timed exercise, we applied a systems biology approach. We mapped and compared global metabolite responses of seven different mouse tissues and serum after an acute exercise bout performed at different times of the day. Comparative analyses of intra- and inter-tissue metabolite dynamics, including temporal profiling and blood sampling across liver and hindlimb muscles, uncovered an unbiased view of local and systemic metabolic responses to exercise unique to time of day. This comprehensive atlas of exercise metabolism provides clarity and physiological context regarding the production and distribution of canonical and novel time-dependent exerkine metabolites, such as 2-hydroxybutyrate (2-HB), and reveals insight into the health-promoting benefits of exercise on metabolism.
    Keywords:  2-hydroxybutyrate; arteriovenous metabolomics; circadian rhythms; exercise metabolism; exerkines; metabolomics; multitissue analysis
    DOI:  https://doi.org/10.1016/j.cmet.2021.12.016
  19. Nat Commun. 2022 Jan 11. 13(1): 208
    Age influences on the molecular presentation of tumours.
    Constance H Li, Syed Haider, Paul C Boutros.
      Cancer is often called a disease of aging. There are numerous ways in which cancer epidemiology and behaviour change with the age of the patient. The molecular bases for these relationships remain largely underexplored. To characterise them, we analyse age-associations in the nuclear and mitochondrial somatic mutational landscape of 20,033 tumours across 35 tumour-types. Age influences both the number of mutations in a tumour (0.077 mutations per megabase per year) and their evolutionary timing. Specific mutational signatures are associated with age, reflecting differences in exogenous and endogenous oncogenic processes such as a greater influence of tobacco use in the tumours of younger patients, but higher activity of DNA damage repair signatures in those of older patients. We find that known cancer driver genes such as CDKN2A and CREBBP are mutated in age-associated frequencies, and these alter the transcriptome and predict for clinical outcomes. These effects are most striking in brain cancers where alterations like SUFU loss and ATRX mutation are age-dependent prognostic biomarkers. Using three cancer datasets, we show that age shapes the somatic mutational landscape of cancer, with clinical implications.
    DOI:  https://doi.org/10.1038/s41467-021-27889-y
  20. Cells. 2021 Dec 23. pii: 38. [Epub ahead of print]11(1):
    Molecular Mechanisms and Regulation of Mammalian Mitophagy.
    Vinay Choubey, Akbar Zeb, Allen Kaasik.
      Mitochondria in the cell are the center for energy production, essential biomolecule synthesis, and cell fate determination. Moreover, the mitochondrial functional versatility enables cells to adapt to the changes in cellular environment and various stresses. In the process of discharging its cellular duties, mitochondria face multiple types of challenges, such as oxidative stress, protein-related challenges (import, folding, and degradation) and mitochondrial DNA damage. They mitigate all these challenges with robust quality control mechanisms which include antioxidant defenses, proteostasis systems (chaperones and proteases) and mitochondrial biogenesis. Failure of these quality control mechanisms leaves mitochondria as terminally damaged, which then have to be promptly cleared from the cells before they become a threat to cell survival. Such damaged mitochondria are degraded by a selective form of autophagy called mitophagy. Rigorous research in the field has identified multiple types of mitophagy processes based on targeting signals on damaged or superfluous mitochondria. In this review, we provide an in-depth overview of mammalian mitophagy and its importance in human health and diseases. We also attempted to highlight the future area of investigation in the field of mitophagy.
    Keywords:  BNIP3; FUNDC1; PARKIN; PINK1; Parkinson’s disease; autophagy; cardiolipin; mitophagy; quality control
    DOI:  https://doi.org/10.3390/cells11010038
  21. Genes Dis. 2022 Jan;9(1): 108-115
    Pancreatic stromal Gremlin 1 expression during pancreatic tumorigenesis.
    Joy M Davis, Binglu Cheng, Madeline M Drake, Qiang Yu, Baibing Yang, Jing Li, Chunhui Liu, Mamoun Younes, Xiurong Zhao, Jennifer M Bailey, Qiang Shen, Tien C Ko, Yanna Cao.
      Chronic pancreatitis (CP) is a major risk factor of pancreatic ductal adenocarcinoma (PDAC). How CP promotes pancreatic oncogenesis remains unclear. A characteristic feature of PDAC is its prominent desmoplasia in the tumor microenvironment, composed of activated fibroblasts and macrophages. Macrophages can be characterized as M1 or M2, with tumor-inhibiting or -promoting functions, respectively. We reported that Gremlin 1 (GREM1), a key pro-fibrogenic factor, is upregulated in the stroma of CP. The current study aimed to investigate the expression of GREM1 and correlation between GREM1 and macrophages within the pancreas during chronic inflammation and the development of PDAC. By mRNA in situ hybridization, we detected GREM1 mRNA expression within α-smooth muscle actin (SMA)-positive fibroblasts of the pancreatic stroma. These designated FibroblastsGrem1+ marginally increased from CP to pancreatic intraepithelial neoplasia (PanIN) and PDAC. Within PDAC, FibroblastsGrem1+ increased with higher pathological tumor stages and in a majority of PDAC subtypes screened. Additionally, FibroblastsGrem1+ positively correlated with total macrophages (MacCD68+) and M2 macrophages (M2CD163+) in PDAC. To begin exploring potential molecular links between FibroblastsGrem1+ and macrophages in PDAC, we examined the expression of macrophage migration inhibitory factor (MIF), an endogenous counteracting molecule of GREM1 and an M1 macrophage promoting factor. By IHC staining of MIF, we found MIF to be expressed by tumor cells, positively correlated with GREM1; by IHC co-staining, we found MIF to be negatively correlated with M2CD163+ expression. Our findings suggest that GREM1 expression by activated fibroblasts may promote PDAC development, and GREM1/MIF may play an important role in macrophage phenotype.
    Keywords:  Fibroblasts; Gremlin 1; Macrophage migration inhibitory factor; Macrophages; Pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.1016/j.gendis.2020.05.001
  22. J Cell Biol. 2022 Mar 07. pii: e202102144. [Epub ahead of print]221(3):
    Active RB causes visible changes in nuclear organization.
    Badri Krishnan, Takaaki Yasuhara, Purva Rumde, Marcello Stanzione, Chenyue Lu, Hanjun Lee, Michael S Lawrence, Lee Zou, Linda T Nieman, Ioannis Sanidas, Nicholas J Dyson.
      RB restricts G1/S progression by inhibiting E2F. Here, we show that sustained expression of active RB, and prolonged G1 arrest, causes visible changes in chromosome architecture that are not directly associated with E2F inhibition. Using FISH probes against two euchromatin RB-associated regions, two heterochromatin domains that lack RB-bound loci, and two whole-chromosome probes, we found that constitutively active RB (ΔCDK-RB) promoted a more diffuse, dispersed, and scattered chromatin organization. These changes were RB dependent, were driven by specific isoforms of monophosphorylated RB, and required known RB-associated activities. ΔCDK-RB altered physical interactions between RB-bound genomic loci, but the RB-induced changes in chromosome architecture were unaffected by dominant-negative DP1. The RB-induced changes appeared to be widespread and influenced chromosome localization within nuclei. Gene expression profiles revealed that the dispersion phenotype was associated with an increased autophagy response. We infer that, after cell cycle arrest, RB acts through noncanonical mechanisms to significantly change nuclear organization, and this reorganization correlates with transitions in cellular state.
    DOI:  https://doi.org/10.1083/jcb.202102144
  23. Mol Cancer. 2022 Jan 12. 21(1): 14
    The role of m6A RNA methylation in cancer metabolism.
    Yuanyuan An, Hua Duan.
      Metabolic reprogramming is one of the main characteristics of malignant tumors, which is due to the flexible changes of cell metabolism that can meet the needs of cell growth and maintain the homeostasis of tissue environments. Cancer cells can obtain metabolic adaptation through a variety of endogenous and exogenous signaling pathways, which can not only promote the growth of malignant cancer cells, but also start the transformation process of cells to adapt to tumor microenvironment. Studies show that m6A RNA methylation is widely involved in the metabolic recombination of tumor cells. In eukaryotes, m6A methylation is the most abundant modification in mRNA, which is involved in almost all the RNA cycle stages, including regulation the transcription, maturation, translation, degradation and stability of mRNA. M6A RNA methylation can be involved in the regulation of physiological and pathological processes, including cancer. In this review, we discuss the role of m6A RNA methylation modification plays in tumor metabolism-related molecules and pathways, aiming to show the importance of targeting m6A in regulating tumor metabolism.
    Keywords:  Cancer; Metabolism reprogramming; The m6A
    DOI:  https://doi.org/10.1186/s12943-022-01500-4
  24. J Cachexia Sarcopenia Muscle. 2022 Jan 10.
    C/EBPβ promotes the expression of atrophy-inducing factors by tumours and is a central regulator of cancer cachexia.
    Hamood AlSudais, Rashida Rajgara, Aisha Saleh, Nadine Wiper-Bergeron.
      BACKGROUND: CCAAT/enhancer-binding protein β (C/EBPβ) is a transcription factor whose high expression in human cancers is associated with tumour aggressiveness and poor outcomes. Most advanced cancer patients will develop cachexia, characterized by loss of skeletal muscle mass. In response to secreted factors from cachexia-inducing tumours, C/EBPβ is stimulated in muscle, leading to both myofibre atrophy and the inhibition of muscle regeneration. Involved in the regulation of immune responses, C/EBPβ induces the expression of many secreted factors, including cytokines. Because tumour-secreted factors drive cachexia and aggressive tumours have higher expression of C/EBPβ, we examined a potential role for C/EBPβ in the expression of tumour-derived cachexia-inducing factors.METHODS: We used gain-of-function and loss-of-function approaches in vitro and in vivo to evaluate the role of tumour C/EBPβ expression on the secretion of cachexia-inducing factors.
    RESULTS: We report that C/EBPβ overexpression up-regulates the expression of 260 secreted protein genes, resulting in a secretome that inhibits myogenic differentiation (-31%, P < 0.05) and myotube maturation [-38% (fusion index) and -25% (myotube diameter), P < 0.05]. We find that knockdown of C/EBPβ in cachexia-inducing Lewis lung carcinoma cells restores myogenic differentiation (+25%, P < 0.0001) and myotube diameter (+90%, P < 0.0001) in conditioned medium experiments and, in vivo, prevents muscle wasting (-51% for small myofibres vs. controls, P < 0.01; +140% for large myofibres, P < 0.01). Conversely, overexpression of C/EBPβ in non-cachectic tumours converts their secretome into a cachexia-inducing one, resulting in reduced myotube diameter (-41%, P < 0.0001, EL4 model) and inhibition of differentiation in culture (-26%, P < 0.01, EL4 model) and muscle wasting in vivo (+98% small fibres, P < 0.001; -76% large fibres, P < 0.001). Comparison of the differently expressed transcripts coding for secreted proteins in C/EBPβ-overexpressing myoblasts with the secretome from 27 different types of human cancers revealed ~18% similarity between C/EBPβ-regulated secreted proteins and those secreted by highly cachectic tumours (brain, pancreatic, and stomach cancers). At the protein level, we identified 16 novel secreted factors that are present in human cancer secretomes and are up-regulated by C/EBPβ. Of these, we tested the effect of three factors (SERPINF1, TNFRSF11B, and CD93) on myotubes and found that all had atrophic potential (-33 to -36% for myotube diameter, P < 0.01).
    CONCLUSIONS: We find that C/EBPβ is necessary and sufficient to induce the secretion of cachexia-inducing factors by cancer cells and loss of C/EBPβ in tumours attenuates muscle atrophy in an animal model of cancer cachexia. Our findings establish C/EBPβ as a central regulator of cancer cachexia and an important therapeutic target.
    Keywords:  CCAAT-enhancer-binding proteins; Cachexia; Carcinoma, Lewis lung; Muscle, skeletal; Muscular atrophy; Secreted proteins
    DOI:  https://doi.org/10.1002/jcsm.12909
  25. Nat Methods. 2022 Jan 13.
    CellRank for directed single-cell fate mapping.
    Marius Lange, Volker Bergen, Michal Klein, Manu Setty, Bernhard Reuter, Mostafa Bakhti, Heiko Lickert, Meshal Ansari, Janine Schniering, Herbert B Schiller, Dana Pe'er, Fabian J Theis.
      Computational trajectory inference enables the reconstruction of cell state dynamics from single-cell RNA sequencing experiments. However, trajectory inference requires that the direction of a biological process is known, largely limiting its application to differentiating systems in normal development. Here, we present CellRank ( https://cellrank.org ) for single-cell fate mapping in diverse scenarios, including regeneration, reprogramming and disease, for which direction is unknown. Our approach combines the robustness of trajectory inference with directional information from RNA velocity, taking into account the gradual and stochastic nature of cellular fate decisions, as well as uncertainty in velocity vectors. On pancreas development data, CellRank automatically detects initial, intermediate and terminal populations, predicts fate potentials and visualizes continuous gene expression trends along individual lineages. Applied to lineage-traced cellular reprogramming data, predicted fate probabilities correctly recover reprogramming outcomes. CellRank also predicts a new dedifferentiation trajectory during postinjury lung regeneration, including previously unknown intermediate cell states, which we confirm experimentally.
    DOI:  https://doi.org/10.1038/s41592-021-01346-6
  26. Biochem J. 2022 Jan 14. 479(1): 75-90
    The complex interplay between autophagy and cell death pathways.
    Christina Ploumi, Margarita-Elena Papandreou, Nektarios Tavernarakis.
      Autophagy is a universal cellular homeostatic process, required for the clearance of dysfunctional macromolecules or organelles. This self-digestion mechanism modulates cell survival, either directly by targeting cell death players, or indirectly by maintaining cellular balance and bioenergetics. Nevertheless, under acute or accumulated stress, autophagy can also contribute to promote different modes of cell death, either through highly regulated signalling events, or in a more uncontrolled inflammatory manner. Conversely, apoptotic or necroptotic factors have also been implicated in the regulation of autophagy, while specific factors regulate both processes. Here, we survey both earlier and recent findings, highlighting the intricate interaction of autophagic and cell death pathways. We, Furthermore, discuss paradigms, where this cross-talk is disrupted, in the context of disease.
    Keywords:  apoptosis; autophagic cell death; autophagy; cancer; necroptosis; neurodegeneration
    DOI:  https://doi.org/10.1042/BCJ20210450
  27. FEBS J. 2022 Jan 11.
    Targeting Cellular Senescence with Senotherapeutics: Senolytics and Senomorphics.
    Lei Zhang, Louise E Pitcher, Vaishali Prahalad, Laura J Niedernhofer, Paul D Robbins.
      The concept of Geroscience is that since aging is the greatest risk factor for many diseases and conditions, targeting the aging process itself will have the greatest impact on human health. Of the hallmarks of aging, cellular senescence has emerged as a druggable therapeutic target for extending healthspan in model organisms. Cellular senescence is a cell state of irreversible proliferative arrest driven by different types of stress, including oncogene-induced stress. Many senescent cells (SnCs) develop a senescent-associated secretory phenotype (SASP) comprising of pro-inflammatory cytokines, chemokines, proteases, bioactive lipids, inhibitory molecules, extracellular vesicles, metabolites, lipids and other factors, able to promote chronic inflammation and tissue dysfunction. SnCs upregulate senescent cell anti-apoptotic pathways (SCAPs) that prevent them from dying despite the accumulation of damage to DNA and other organelles. These SCAPs and other pathways altered in SnCs represent therapeutic targets for the development of senotherapeutic drugs that induce apoptosis of SnCs specifically, termed senolytics, or suppress markers of senescence, in particular the SASP, termed senomorphics. Here, we review the current state of the development of senolytics and senomorphics for the treatment of age-related diseases and disorders and extension of healthy longevity. In addition, the challenges of documenting senolytic and senomorphic activity in pre-clinical models and the current state of the clinical application of the different senotherapeutics will be discussed.
    Keywords:  PROTACs; SASP; SCAP; Senescence; aging; drug screening; geroscience; pro-drugs; senolytics; senomorphics
    DOI:  https://doi.org/10.1111/febs.16350
  28. Nat Aging. 2021 Oct;1(10): 962-973
    An inducible p21-Cre mouse model to monitor and manipulate p21-highly-expressing senescent cells in vivo.
    Binsheng Wang, Lichao Wang, Nathan S Gasek, Yueying Zhou, Taewan Kim, Chun Guo, Evan R Jellison, Laura Haynes, Sumit Yadav, Tamar Tchkonia, George A Kuchel, James L Kirkland, Ming Xu.
      The role of senescent cells has been implicated in various tissue dysfunction associated with aging, obesity, and other pathological conditions. Currently, most transgenic mouse models only target p16 Ink4a-highly-expressing (p16 high) cells. Here, we generated a p21-Cre mouse model, containing a p21 promoter driving inducible Cre, enabling us to examine p21 Cip1-highly-expressing (p21 high) cells, a previously unexplored cell population exhibiting several characteristics typical of senescent cells. By crossing p21-Cre mice with different floxed mice, we managed to monitor, sort, image, eliminate, or modulate p21 high cells in vivo. We showed p21 high cells can be induced by various conditions, and percentages of p21 high cells varied from 1.5 to 10% across different tissues in 23-month-old mice. Intermittent clearance of p21 high cells improved physical function in 23-month-old mice. Our study demonstrates that the p21-Cre mouse model is a valuable and powerful tool for studying p21 high cells to further understand the biology of senescent cells.
    DOI:  https://doi.org/10.1038/s43587-021-00107-6
  29. EMBO J. 2022 Jan 13. e106825
    Hypophosphorylated pRb knock-in mice exhibit hallmarks of aging and vitamin C-preventable diabetes.
    Zhe Jiang, Huiqin Li, Stephanie A Schroer, Veronique Voisin, YoungJun Ju, Marek Pacal, Natalie Erdmann, Wei Shi, Philip E D Chung, Tao Deng, Nien-Jung Chen, Giovanni Ciavarra, Alessandro Datti, Tak W Mak, Lea Harrington, Frederick A Dick, Gary D Bader, Rod Bremner, Minna Woo, Eldad Zacksenhaus.
      Despite extensive analysis of pRB phosphorylation in vitro, how this modification influences development and homeostasis in vivo is unclear. Here, we show that homozygous Rb∆K4 and Rb∆K7 knock-in mice, in which either four or all seven phosphorylation sites in the C-terminal region of pRb, respectively, have been abolished by Ser/Thr-to-Ala substitutions, undergo normal embryogenesis and early development, notwithstanding suppressed phosphorylation of additional upstream sites. Whereas Rb∆K4 mice exhibit telomere attrition but no other abnormalities, Rb∆K7 mice are smaller and display additional hallmarks of premature aging including infertility, kyphosis, and diabetes, indicating an accumulative effect of blocking pRb phosphorylation. Diabetes in Rb∆K7 mice is insulin-sensitive and associated with failure of quiescent pancreatic β-cells to re-enter the cell cycle in response to mitogens, resulting in induction of DNA damage response (DDR), senescence-associated secretory phenotype (SASP), and reduced pancreatic islet mass and circulating insulin level. Pre-treatment with the epigenetic regulator vitamin C reduces DDR, increases cell cycle re-entry, improves islet morphology, and attenuates diabetes. These results have direct implications for cell cycle regulation, CDK-inhibitor therapeutics, diabetes, and longevity.
    Keywords:  aging; diabetes; knock-in mice; pRB; retinoblastoma; senescence; vitamin C
    DOI:  https://doi.org/10.15252/embj.2020106825
  30. Autophagy. 2022 Jan 09. 1-3
    GAK and PRKCD kinases regulate basal mitophagy.
    Michael J Munson, Benan J Mathai, Matthew Yoke Wui Ng, Laura Trachsel-Moncho, Laura R de la Ballina, Anne Simonsen.
      The removal of mitochondria in a programmed or stress-induced manner is essential for maintaining cellular homeostasis. To date, much research has focused upon stress-induced mitophagy that is largely regulated by the E3 ligase PRKN, with limited insight into the mechanisms regulating basal "housekeeping" mitophagy levels in different model organisms. Using iron chelation as an inducer of PRKN-independent mitophagy, we recently screened an siRNA library of lipid-binding proteins and determined that two kinases, GAK and PRKCD, act as positive regulators of PRKN-independent mitophagy. We demonstrate that PRKCD is localized to mitochondria and regulates recruitment of ULK1-ATG13 upon induction of mitophagy. GAK activity, by contrast, modifies the mitochondrial network and lysosomal morphology that compromise efficient transport of mitochondria for degradation. Impairment of either kinase in vivo blocks basal mitophagy, demonstrating the biological relevance of our findings.Abbreviations: CCCP: carbonyl cyanide-m-chlorophenyl hydrazone; DFP: deferiprone; GAK: cyclin G associated kinase; HIF1A: hypoxia inducible factor 1 subunit alpha; PRKC/PKC: protein kinase C; PRKCD: protein kinase C delta; PRKN: parkin RBR E3 ubiquitin protein ligase.
    Keywords:  Cyclin-G-associated kinase; GAK; PKC; PRKCD; PRKN; mitophagy; protein kinase C
    DOI:  https://doi.org/10.1080/15548627.2021.2015154
  31. Int J Mol Sci. 2021 Dec 21. pii: 7. [Epub ahead of print]23(1):
    Cytosolic Quality Control of Mitochondrial Protein Precursors-The Early Stages of the Organelle Biogenesis.
    Anna M Lenkiewicz, Magda Krakowczyk, Piotr Bragoszewski.
      With few exceptions, proteins that constitute the proteome of mitochondria originate outside of this organelle in precursor forms. Such protein precursors follow dedicated transportation paths to reach specific parts of mitochondria, where they complete their maturation and perform their functions. Mitochondrial precursor targeting and import pathways are essential to maintain proper mitochondrial function and cell survival, thus are tightly controlled at each stage. Mechanisms that sustain protein homeostasis of the cytosol play a vital role in the quality control of proteins targeted to the organelle. Starting from their synthesis, precursors are constantly chaperoned and guided to reduce the risk of premature folding, erroneous interactions, or protein damage. The ubiquitin-proteasome system provides proteolytic control that is not restricted to defective proteins but also regulates the supply of precursors to the organelle. Recent discoveries provide evidence that stress caused by the mislocalization of mitochondrial proteins may contribute to disease development. Precursors are not only subject to regulation but also modulate cytosolic machinery. Here we provide an overview of the cellular pathways that are involved in precursor maintenance and guidance at the early cytosolic stages of mitochondrial biogenesis. Moreover, we follow the circumstances in which mitochondrial protein import deregulation disturbs the cellular balance, carefully looking for rescue paths that can restore proteostasis.
    Keywords:  mitochondrial biogenesis; molecular chaperone; proteasome; protein degradation; protein precursor; protein transport; proteostasis; quality control; ubiquitin
    DOI:  https://doi.org/10.3390/ijms23010007
  32. Elife. 2022 Jan 10. pii: e71137. [Epub ahead of print]11
    Functional CDKN2A assay identifies frequent deleterious alleles misclassified as variants of uncertain significance.
    Hirokazu Kimura, Raymond M Paranal, Neha Nanda, Laura D Wood, James R Eshleman, Ralph H Hruban, Michael G Goggins, Alison P Klein, Nicholas Jason Roberts.
      Pathogenic germline CDKN2A variants are associated with an increased risk of pancreatic ductal adenocarcinoma (PDAC). CDKN2A variants of uncertain significance (VUSs) are reported in up to 4.3% of patients with PDAC and result in significant uncertainty for patients and their family members as an unknown fraction are functionally deleterious, and therefore, likely pathogenic. Functional characterization of CDKN2A VUSs is needed to reclassify variants and inform clinical management. 29 germline CDKN2A VUSs previously reported in patients with PDAC or in ClinVar were evaluated using a validated in vitro cell proliferation assay. 12 of the 29 CDKN2A VUSs were functionally deleterious (11 VUSs) or potentially functionally deleterious (1 VUS) and were reclassified as likely pathogenic variants. Thus, over 40% of CDKN2A VUSs identified in patients with PDAC are functionally deleterious and likely pathogenic. When incorporating VUSs found to be functionally deleterious, and reclassified as likely pathogenic, the prevalence of pathogenic/likely pathogenic CDKN2A in patients with PDAC reported in the published literature is increased to up to 4.1% of patients, depending on family history. Therefore, CDKN2A VUSs may play a significant, unappreciated role in risk of pancreatic cancer. These findings have significant implications for the counselling and care of patients and their relatives.
    Keywords:  cancer biology; genetics; genomics; human
    DOI:  https://doi.org/10.7554/eLife.71137
  33. Proc Natl Acad Sci U S A. 2022 Jan 18. pii: e2105171119. [Epub ahead of print]119(3):
    Genome-wide screens identify specific drivers of mutant hTERT promoters.
    Raghuvaran Shanmugam, Mert Burak Ozturk, Joo-Leng Low, Semih Can Akincilar, Joelle Yi Heng Chua, Matan Thangavelu Thangavelu, Giridharan Periyasamy, Ramanuj DasGupta, Vinay Tergaonkar.
      Cancer-specific hTERT promoter mutations reported in 19% of cancers result in enhanced telomerase activity. Understanding the distinctions between transcriptional regulation of wild-type (WT) and mutant (Mut) hTERT promoters may open up avenues for development of inhibitors which specially block hTERT expression in cancer cells. To comprehensively identify physiological regulators of WT- or Mut-hTERT promoters, we generated several isogenic reporter cells driven by endogenous hTERT loci. Genome-wide CRISPR-Cas9 and small interfering RNA screens using these isogenic reporter lines identified specific regulators of Mut-hTERT promoters. We validate and characterize one of these hits, namely, MED12, a kinase subunit of mediator complex. We demonstrate that MED12 specifically drives expression of hTERT from the Mut-hTERT promoter by mediating long-range chromatin interaction between the proximal Mut-hTERT promoter and T-INT1 distal regulatory region 260 kb upstream. Several hits identified in our screens could serve as potential therapeutic targets, inhibition of which may specifically block Mut-hTERT promoter driven telomerase reactivation in cancers.
    Keywords:  TERT; cancer; chromatin; telomerase
    DOI:  https://doi.org/10.1073/pnas.2105171119
  34. Nat Commun. 2022 Jan 10. 13(1): 124
    Lipidomic profiling of human serum enables detection of pancreatic cancer.
    Denise Wolrab, Robert Jirásko, Eva Cífková, Marcus Höring, Ding Mei, Michaela Chocholoušková, Ondřej Peterka, Jakub Idkowiak, Tereza Hrnčiarová, Ladislav Kuchař, Robert Ahrends, Radana Brumarová, David Friedecký, Gabriel Vivo-Truyols, Pavel Škrha, Jan Škrha, Radek Kučera, Bohuslav Melichar, Gerhard Liebisch, Ralph Burkhardt, Markus R Wenk, Amaury Cazenave-Gassiot, Petr Karásek, Ivo Novotný, Kristína Greplová, Roman Hrstka, Michal Holčapek.
      Pancreatic cancer has the worst prognosis among all cancers. Cancer screening of body fluids may improve the survival time prognosis of patients, who are often diagnosed too late at an incurable stage. Several studies report the dysregulation of lipid metabolism in tumor cells, suggesting that changes in the blood lipidome may accompany tumor growth. Here we show that the comprehensive mass spectrometric determination of a wide range of serum lipids reveals statistically significant differences between pancreatic cancer patients and healthy controls, as visualized by multivariate data analysis. Three phases of biomarker discovery research (discovery, qualification, and verification) are applied for 830 samples in total, which shows the dysregulation of some very long chain sphingomyelins, ceramides, and (lyso)phosphatidylcholines. The sensitivity and specificity to diagnose pancreatic cancer are over 90%, which outperforms CA 19-9, especially at an early stage, and is comparable to established diagnostic imaging methods. Furthermore, selected lipid species indicate a potential as prognostic biomarkers.
    DOI:  https://doi.org/10.1038/s41467-021-27765-9
  35. Cell Rep. 2022 Jan 11. pii: S2211-1247(21)01745-9. [Epub ahead of print]38(2): 110236
    Reprogramming of nucleotide metabolism by interferon confers dependence on the replication stress response pathway in pancreatic cancer cells.
    Evan R Abt, Thuc M Le, Amanda M Dann, Joseph R Capri, Soumya Poddar, Vincent Lok, Luyi Li, Keke Liang, Amanda L Creech, Khalid Rashid, Woosuk Kim, Nanping Wu, Jing Cui, Arthur Cho, Hailey Rose Lee, Ethan W Rosser, Jason M Link, Johannes Czernin, Ting-Ting Wu, Robert Damoiseaux, David W Dawson, Timothy R Donahue, Caius G Radu.
      We determine that type I interferon (IFN) response biomarkers are enriched in a subset of pancreatic ductal adenocarcinoma (PDAC) tumors; however, actionable vulnerabilities associated with IFN signaling have not been systematically defined. Integration of a phosphoproteomic analysis and a chemical genomics synergy screen reveals that IFN activates the replication stress response kinase ataxia telangiectasia and Rad3-related protein (ATR) in PDAC cells and sensitizes them to ATR inhibitors. IFN triggers cell-cycle arrest in S-phase, which is accompanied by nucleotide pool insufficiency and nucleoside efflux. In combination with IFN, ATR inhibitors induce lethal DNA damage and downregulate nucleotide biosynthesis. ATR inhibition limits the growth of PDAC tumors in which IFN signaling is driven by stimulator of interferon genes (STING). These results identify a cross talk between IFN, DNA replication stress response networks, and nucleotide metabolism while providing the rationale for targeted therapeutic interventions that leverage IFN signaling in tumors.
    Keywords:  STING; interferon; nucleotide metabolism; pancreas cancer; replication stress
    DOI:  https://doi.org/10.1016/j.celrep.2021.110236
  36. Cells. 2022 Jan 04. pii: 153. [Epub ahead of print]11(1):
    The Impact of Exercise on Telomere Length, DNA Methylation and Metabolic Footprints.
    Sandra Haupt, Tobias Niedrist, Harald Sourij, Stephan Schwarzinger, Othmar Moser.
      Aging as a major risk factor influences the probability of developing cancer, cardiovascular disease and diabetes, amongst others. The underlying mechanisms of disease are still not fully understood, but research suggests that delaying the aging process could ameliorate these pathologies. A key biological process in aging is cellular senescence which is associated with several stressors such as telomere shortening or enhanced DNA methylation. Telomere length as well as DNA methylation levels can be used as biological age predictors which are able to detect excessive acceleration or deceleration of aging. Analytical methods examining aging are often not suitable, expensive, time-consuming or require a high level of technical expertise. Therefore, research focusses on combining analytical methods which have the potential to simultaneously analyse epigenetic, genomic as well as metabolic changes.
    Keywords:  DNA methylation; exercise; metabolism; metabolomics; telomere length
    DOI:  https://doi.org/10.3390/cells11010153
  37. Front Cell Dev Biol. 2021 ;9 761807
    Microfluidic Platforms for High-Throughput Pancreatic Ductal Adenocarcinoma Organoid Culture and Drug Screening.
    Marlene Geyer, Karla Queiroz.
      Pancreatic Ductal Adenocarcinoma (PDAC), the most common pancreatic cancer type, is believed to become the second leading cause of cancer-related deaths by 2030 with mortality rates of up to 93%. It is often detected at a late stage due to lacking symptoms, and therefore surgical removal of the tumor is the only treatment option for patients. Only 20% of the tumors are resectable, mainly due to early metastasis. Therefore, for 80% of cases chemotherapeutic treatment is the leading therapy for patients. PDAC is characterized by high-density stroma which induces hypoxic conditions and high interstitial pressure. These factors impact carcinogenesis and progression of PDAC and support the formation of an immunosuppressive microenvironment that renders this tumor type refractory to immunotherapies. Most in vitro PDAC models have limited translational relevance, as these fail to recapitulate relevant aspects of PDAC complexity. Altogether, there is an urgent need for novel and innovative PDAC modeling platforms. Here, we discuss the relevance of microfluidic and organoid technologies as platforms for modeling bio- and physicochemical features of PDAC and as translational models that enable high-throughput phenotypic drug screenings, while also allowing for the development of novel personalized models used to identify treatment responsive patient subsets.
    Keywords:  PDAC; drug screening; organ-on-a chip; organoids; tumor microenvionment
    DOI:  https://doi.org/10.3389/fcell.2021.761807
  38. Cancers (Basel). 2021 Dec 31. pii: 201. [Epub ahead of print]14(1):
    Rethinking the TNM Classification Regarding Direct Lymph Node Invasion in Pancreatic Ductal Adenocarcinoma.
    Fiona Speichinger, Mihnea P Dragomir, Simon Schallenberg, Florian N Loch, Claudius E Degro, Ann-Kathrin Baukloh, Lisa Hartmann, Ioannis Pozios, Christian Schineis, Georgios Antonios Margonis, Johannes C Lauscher, Katharina Beyer, Carsten Kamphues.
      Mechanisms of lymph node invasion seem to play a prognostic role in pancreatic ductal adenocarcinoma (PDAC) after resection. However, the 8th edition of the TNM classification of the American Joint Committee on Cancer (AJCC) does not consider this. The aim of this study was to analyse the prognostic role of different mechanisms of lymph node invasion on PDAC. One hundred and twenty-two patients with resected PDAC were examined. We distinguished three groups: direct (per continuitatem, Nc) from the main tumour, metastasis (Nm) without any contact to the main tumour, and a mixed mechanism (Ncm). Afterwards, the prognostic power of the different groups was analysed concerning overall survival (OS). In total, 20 patients displayed direct lymph node invasion (Nc = 16.4%), 44 were classed as Nm (36.1%), and 21 were classed as Ncm (17.2%). The difference in OS was not statistically significant between N0 (no lymph node metastasis, n = 37) and Nc (p = 0.134), while Nm had worse OS than N0 (p < 0.001). Direct invasion alone had no statistically significant effect on OS (p = 0.885). Redefining the N0 stage by including Nc patients showed a more precise OS prediction among N stages (p = 0.001 vs. p = 0.002). Nc was more similar to N0 than to Nm; hence, we suggest a rethinking of TNM classification based on the mechanisms of lymph node metastases in PDAC. Overall, this novel classification is more precise.
    Keywords:  TNM classification; direct lymph node invasion; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.3390/cancers14010201
  39. Nat Biotechnol. 2022 Jan 13.
    Cell2location maps fine-grained cell types in spatial transcriptomics.
    Vitalii Kleshchevnikov, Artem Shmatko, Emma Dann, Alexander Aivazidis, Hamish W King, Tong Li, Rasa Elmentaite, Artem Lomakin, Veronika Kedlian, Adam Gayoso, Mika Sarkin Jain, Jun Sung Park, Lauma Ramona, Elizabeth Tuck, Anna Arutyunyan, Roser Vento-Tormo, Moritz Gerstung, Louisa James, Oliver Stegle, Omer Ali Bayraktar.
      Spatial transcriptomic technologies promise to resolve cellular wiring diagrams of tissues in health and disease, but comprehensive mapping of cell types in situ remains a challenge. Here we present сell2location, a Bayesian model that can resolve fine-grained cell types in spatial transcriptomic data and create comprehensive cellular maps of diverse tissues. Cell2location accounts for technical sources of variation and borrows statistical strength across locations, thereby enabling the integration of single-cell and spatial transcriptomics with higher sensitivity and resolution than existing tools. We assessed cell2location in three different tissues and show improved mapping of fine-grained cell types. In the mouse brain, we discovered fine regional astrocyte subtypes across the thalamus and hypothalamus. In the human lymph node, we spatially mapped a rare pre-germinal center B cell population. In the human gut, we resolved fine immune cell populations in lymphoid follicles. Collectively, our results present сell2location as a versatile analysis tool for mapping tissue architectures in a comprehensive manner.
    DOI:  https://doi.org/10.1038/s41587-021-01139-4
  40. Clin Exp Metastasis. 2022 Jan 09.
    The effect of the low stromal ratio induced by neoadjuvant chemotherapy on recurrence patterns in borderline resectable pancreatic ductal adenocarcinoma.
    Kenji Kawahara, Shigetsugu Takano, Katsunori Furukawa, Tsukasa Takayashiki, Satoshi Kuboki, Masayuki Ohtsuka.
      The optimal regimens of neoadjuvant chemotherapy (NAC) and its biological and physiological modification of the tumor microenvironment (TME) in patients with borderline resectable pancreatic ductal adenocarcinoma (BR PDAC) remain unknown. A deeper understanding of the complex stromal biology of the TME will identify new avenues to establish treatment strategies for PDAC patients. Herein, we sought to clarify whether stromal remodeling by NAC affects recurrence patterns and prognosis in BR PDAC patients. We retrospectively analyzed data from 104 BR PDAC patients who underwent pancreatectomy with or without NAC (upfront surgery [UpS], n = 44; gemcitabine + nab-paclitaxel [GnP], n = 28; and gemcitabine + S-1 [GS], n = 32) to assess the correlations of treatment with early recurrence, the stromal ratio, and Ki-67 levels. Eighty-six patients experienced recurrence, and those with liver metastasis had significantly shorter recurrence-free survival than those with other recurrence patterns. The frequency of liver metastasis was significantly higher in patients with a low stromal ratio than in those with a high stromal ratio in the NAC group but not in the UpS group. Patients in the GnP group had significantly higher Ki-67 than those in the GS and UpS groups. A low stromal ratio was positively correlated with high Ki-67 in the NAC group but not in the UpS group. The low stromal ratio induced by NAC promoted early liver metastasis in patients with BR PDAC. Our findings provide new insights into the complexity of stromal biology, leading to consideration of the optimal NAC regimen.
    Keywords:  Gemcitabine plus nab-paclitaxel; Liver metastasis; Neoadjuvant chemotherapy; Pancreatic ductal adenocarcinoma; Stroma
    DOI:  https://doi.org/10.1007/s10585-021-10142-7
  41. Nat Rev Drug Discov. 2022 Jan 13.
    Preclinical cancer research suffers another reproducibility blow.
    Asher Mullard.
      
    DOI:  https://doi.org/10.1038/d41573-022-00012-6
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