bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2021‒06‒13
twenty-four papers selected by
Kıvanç Görgülü
Technical University of Munich
  1. Single-cell lineage tracing of metastatic cancer reveals selection of hybrid EMT states.
  2. Targeting glucose metabolism sensitizes pancreatic cancer to MEK inhibition.
  3. Tissue mechanics in stem cell fate, development, and cancer.
  4. The Epithelial-to-Mesenchymal Transition (EMT) in Development and Cancer.
  5. Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8+ T cells in tumors.
  6. Senolytics reduce coronavirus-related mortality in old mice.
  7. RAL GTPases mediate EGFR-driven intestinal stem cell proliferation and tumourigenesis.
  8. Pharmacological or genetic inhibition of iNOS prevents cachexia-mediated muscle wasting and its associated metabolism defects.
  9. Targeting the SHP2 phosphatase promotes vascular damage and inhibition of tumor growth.
  10. New insights into pancreatic cancer: notes from a virtual meeting.
  11. High-fat diet-activated fatty acid oxidation mediates intestinal stemness and tumorigenicity.
  12. Association of losartan with outcomes in metastatic pancreatic cancer patients treated with chemotherapy.
  13. Exercise reduces circulating biomarkers of cellular senescence in humans.
  14. Aneuploid senescent cells activate NF-κB to promote their immune clearance by NK cells.
  15. Cancer stem cell-immune cell crosstalk in tumour progression.
  16. Cancer-induced muscle atrophy is determined by intrinsic muscle oxidative capacity.
  17. Mitochondrial mistranslation modulated by metabolic stress causes cardiovascular disease and reduced lifespan.
  18. The mitochondrial NADH pool is involved in hydrogen sulfide signaling and stimulation of aerobic glycolysis.
  19. PRMT5-mediated arginine methylation activates AKT kinase to govern tumorigenesis.
  20. Preoperative serum ADAM12 levels as a stromal marker for overall survival and benefit of adjuvant therapy in patients with resected pancreatic and periampullary cancer.
  21. Measuring the effect of drug treatments on primary human CD8+ T cell activation and cytolytic potential.
  22. Suppression of tumor-associated neutrophils by lorlatinib attenuates pancreatic cancer growth and improves treatment with immune checkpoint blockade.
  23. Phase II Study of 5-Fluorouracil, Oxaliplatin plus Dasatinib (FOLFOX-D) in First-Line Metastatic Pancreatic Adenocarcinoma.
  24. Regulation of the one carbon folate cycle as a shared metabolic signature of longevity.
  1. Cancer Cell. 2021 May 28. pii: S1535-6108(21)00271-3. [Epub ahead of print]
    Single-cell lineage tracing of metastatic cancer reveals selection of hybrid EMT states.
    Kamen P Simeonov, China N Byrns, Megan L Clark, Robert J Norgard, Beth Martin, Ben Z Stanger, Jay Shendure, Aaron McKenna, Christopher J Lengner.
      The underpinnings of cancer metastasis remain poorly understood, in part due to a lack of tools for probing their emergence at high resolution. Here we present macsGESTALT, an inducible CRISPR-Cas9-based lineage recorder with highly efficient single-cell capture of both transcriptional and phylogenetic information. Applying macsGESTALT to a mouse model of metastatic pancreatic cancer, we recover ∼380,000 CRISPR target sites and reconstruct dissemination of ∼28,000 single cells across multiple metastatic sites. We find that cells occupy a continuum of epithelial-to-mesenchymal transition (EMT) states. Metastatic potential peaks in rare, late-hybrid EMT states, which are aggressively selected from a predominately epithelial ancestral pool. The gene signatures of these late-hybrid EMT states are predictive of reduced survival in both human pancreatic and lung cancer patients, highlighting their relevance to clinical disease progression. Finally, we observe evidence for in vivo propagation of S100 family gene expression across clonally distinct metastatic subpopulations.
    Keywords:  CRISPR; EMT; S100; barcoding; epithelial-to-mesenchymal transition; evolving barcodes; ineage tracing; metastasis; phylogenetics; single cell
    DOI:  https://doi.org/10.1016/j.ccell.2021.05.005
  2. Cancer Res. 2021 Jun 11. pii: canres.3792.2020. [Epub ahead of print]
    Targeting glucose metabolism sensitizes pancreatic cancer to MEK inhibition.
    Liang Yan, Bo Tu, Jun Yao, Jing Gong, Alessandro Carugo, Christopher A Bristow, Qiuyun Wang, Cihui Zhu, Bingbing Dai, Ya'an Kang, Leng Han, Ningping Feng, Yanqing Jin, Jason Fleming, Timothy P Heffernan, Wantong Yao, Haoqiang Ying.
      Pancreatic ductal adenocarcinoma (PDAC) is almost universally lethal. A critical unmet need exists to explore essential susceptibilities in PDAC and identify druggable targets to improve PDAC treatment. KRAS mutations dominate the genetic landscape of PDAC and lead to activation of multiple downstream pathways and cellular processes. Here, we investigated the requirement of these pathways for tumor maintenance using an inducible KrasG12D-driven PDAC mouse model (iKras model), identifying that RAF-MEK-MAPK signaling is the major effector for oncogenic KRAS-mediated tumor maintenance. However, consistent with previous studies, MEK inhibition had minimal therapeutic effect as a single agent for PDAC in vitro and in vivo. Although MEK inhibition partially downregulated transcription of glycolysis genes, it failed to suppress glycolytic flux in PDAC cells, which is a major metabolic effector of oncogenic KRAS. Accordingly, an in vivo genetic screen identified multiple glycolysis genes as potential targets that may sensitize tumor cells to MEK inhibition. Inhibition of glucose metabolism with low dose 2-deoxyglucose in combination with a MEK inhibitor induced apoptosis in KrasG12D-driven PDAC cells in vitro. The combination also inhibited xenograft PDAC tumor growth and prolonged overall survival in a genetically engineered PDAC mouse model. Molecular and metabolic analyses indicated that co-targeting glycolysis and MAPK signaling results in apoptosis via induction of lethal ER stress. Together, our work suggests that combined inhibition of glycolysis and the MAPK pathway may serve as an effective approach to target KRAS-driven PDAC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-3792
  3. Dev Cell. 2021 Jun 03. pii: S1534-5807(21)00440-8. [Epub ahead of print]
    Tissue mechanics in stem cell fate, development, and cancer.
    Mary-Kate Hayward, Jonathon M Muncie, Valerie M Weaver.
      Cells in tissues experience a plethora of forces that regulate their fate and modulate development and homeostasis. Cells sense mechanical cues through localized mechanoreceptors or by influencing cytoskeletal or plasma membrane organization. Cells translate force and modulate their behavior through a process termed mechanotransduction. Cells tune their tension upon exposure to chronic force by engaging cellular machinery that modulates actin tension, which in turn stimulates matrix remodeling and stiffening and alters cell-cell adhesions until cells achieve a state of tensional homeostasis. Loss of tensional homeostasis can be induced through oncogene activity and/or tissue fibrosis, accompanies tumor progression, and is associated with increased cancer risk. The mechanical stresses that develop in tumors can also foster the mesenchymal-like transdifferentiation of cells to induce a stem-like phenotype that contributes to their aggression, metastatic dissemination, and treatment resistance. Thus, strategies that ameliorate tumor mechanics may comprise an effective strategy to prevent aggressive tumor behavior.
    DOI:  https://doi.org/10.1016/j.devcel.2021.05.011
  4. Annu Rev Cancer Biol. 2020 Mar;4 197-220
    The Epithelial-to-Mesenchymal Transition (EMT) in Development and Cancer.
    Alexandre Francou, Kathryn V Anderson.
      Epithelial-to-mesenchymal transitions (EMTs) are complex cellular processes where cells undergo dramatic changes in signaling, transcriptional programming, and cell shape, while directing the exit of cells from the epithelium and promoting migratory properties of the resulting mesenchyme. EMTs are essential for morphogenesis during development and are also a critical step in cancer progression and metastasis formation. Here we provide an overview of the molecular regulation of the EMT process during embryo development, focusing on chick and mouse gastrulation and neural crest development. We go on to describe how EMT regulators participate in the progression of pancreatic and breast cancer in mouse models, and discuss the parallels with developmental EMTs and how these help to understand cancer EMTs. We also highlight the differences between EMTs in tumor and in development to arrive at a broader view of cancer EMT. We conclude by discussing how further advances in the field will rely on in vivo dynamic imaging of the cellular events of EMT.
    Keywords:  Epithelial-to-Mesenchymal Transition; breast cancer; cancer progression; gastrulation; intravital imaging; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.1146/annurev-cancerbio-030518-055425
  5. Immunity. 2021 May 28. pii: S1074-7613(21)00209-0. [Epub ahead of print]
    Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8+ T cells in tumors.
    Shihao Xu, Omkar Chaudhary, Patricia Rodríguez-Morales, Xiaoli Sun, Dan Chen, Roberta Zappasodi, Ziyan Xu, Antonio F M Pinto, April Williams, Isabell Schulze, Yagmur Farsakoglu, Siva Karthik Varanasi, Jun Siong Low, Wenxi Tang, Haiping Wang, Bryan McDonald, Victoria Tripple, Michael Downes, Ronald M Evans, Nada A Abumrad, Taha Merghoub, Jedd D Wolchok, Maxim N Shokhirev, Ping-Chih Ho, Joseph L Witztum, Brinda Emu, Guoliang Cui, Susan M Kaech.
      A common metabolic alteration in the tumor microenvironment (TME) is lipid accumulation, a feature associated with immune dysfunction. Here, we examined how CD8+ tumor infiltrating lymphocytes (TILs) respond to lipids within the TME. We found elevated concentrations of several classes of lipids in the TME and accumulation of these in CD8+ TILs. Lipid accumulation was associated with increased expression of CD36, a scavenger receptor for oxidized lipids, on CD8+ TILs, which also correlated with progressive T cell dysfunction. Cd36-/- T cells retained effector functions in the TME, as compared to WT counterparts. Mechanistically, CD36 promoted uptake of oxidized low-density lipoproteins (OxLDL) into T cells, and this induced lipid peroxidation and downstream activation of p38 kinase. Inhibition of p38 restored effector T cell functions in vitro, and resolution of lipid peroxidation by overexpression of glutathione peroxidase 4 restored functionalities in CD8+ TILs in vivo. Thus, an oxidized lipid-CD36 axis promotes intratumoral CD8+ T cell dysfunction and serves as a therapeutic avenue for immunotherapies.
    Keywords:  CD36; CD8(+) T cells; lipid peroxidation; oxidized lipids; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.immuni.2021.05.003
  6. Science. 2021 Jun 08. pii: eabe4832. [Epub ahead of print]
    Senolytics reduce coronavirus-related mortality in old mice.
    Christina D Camell, Matthew J Yousefzadeh, Yi Zhu, Larissa G P Langhi Prata, Matthew A Huggins, Mark Pierson, Lei Zhang, Ryan D O'Kelly, Tamar Pirtskhalava, Pengcheng Xun, Keisuke Ejima, Ailing Xue, Utkarsh Tripathi, Jair Machado Espindola-Netto, Nino Giorgadze, Elizabeth J Atkinson, Christina L Inman, Kurt O Johnson, Stephanie H Cholensky, Timothy W Carlson, Nathan K LeBrasseur, Sundeep Khosla, M Gerard O'Sullivan, David B Allison, Stephen C Jameson, Alexander Meves, Ming Li, Y S Prakash, Sergio E Chiarella, Sara E Hamilton, Tamara Tchkonia, Laura J Niedernhofer, James L Kirkland, Paul D Robbins.
      The COVID-19 pandemic has revealed the pronounced vulnerability of the elderly and chronically-ill to SARS-CoV-2-induced morbidity and mortality. Cellular senescence contributes to inflammation, multiple chronic diseases, and age-related dysfunction, but effects on responses to viral infection are unclear. Here, we demonstrate that senescent cells (SnC) become hyper-inflammatory in response to pathogen-associated molecular patterns (PAMPs), including SARS-CoV-2 Spike protein-1, increasing expression of viral entry proteins and reducing anti-viral gene expression in non-SnCs through a paracrine mechanism. Old mice acutely infected with pathogens that included a SARS-CoV-2-related mouse β-coronavirus experienced increased senescence and inflammation with nearly 100% mortality. Targeting SnCs using senolytic drugs before or after pathogen exposure significantly reduced mortality, cellular senescence, and inflammatory markers and increased anti-viral antibodies. Thus, reducing the SnC burden in diseased or aged individuals should enhance resilience and reduce mortality following viral infection, including SARS-CoV-2.
    DOI:  https://doi.org/10.1126/science.abe4832
  7. Elife. 2021 Jun 07. pii: e63807. [Epub ahead of print]10
    RAL GTPases mediate EGFR-driven intestinal stem cell proliferation and tumourigenesis.
    Máté Nászai, Karen Bellec, Yachuan Yu, Alvaro Román-Fernández, Emma Sandilands, Joel Johansson, Andrew D Campbell, Jim C Norman, Owen J Sansom, David M Bryant, Julia B Cordero.
      RAS-like (RAL) GTPases function in Wnt signalling-dependent intestinal stem cell proliferation and regeneration. Whether RAL proteins work as canonical RAS effectors in the intestine, and the mechanisms of how they contribute to tumourigenesis remain unclear. Here, we show that RAL GTPases are necessary and sufficient to activate EGFR/MAPK signalling in the intestine, via induction of EGFR internalisation. Knocking down Drosophila RalA from intestinal stem and progenitor cells leads to increased levels of plasma membrane-associated EGFR and decreased MAPK pathway activation. Importantly, in addition to impacting stem cell proliferation during damage-induced intestinal regeneration, this role of RAL GTPases impacts on EGFR-dependent tumorigenic growth in the intestine and in human mammary epithelium. However, the effect of oncogenic RAS in the intestine is independent from RAL function. Altogether, our results reveal previously unrecognised cellular and molecular contexts where RAL GTPases become essential mediators of adult tissue homeostasis and malignant transformation.
    Keywords:  D. melanogaster; cancer biology; human; mouse; regenerative medicine; stem cells
    DOI:  https://doi.org/10.7554/eLife.63807
  8. EMBO Mol Med. 2021 Jun 07. e13591
    Pharmacological or genetic inhibition of iNOS prevents cachexia-mediated muscle wasting and its associated metabolism defects.
    Jason Sadek, Derek T Hall, Bianca Colalillo, Amr Omer, Anne-Marie K Tremblay, Virginie Sanguin-Gendreau, William Muller, Sergio Di Marco, Marco Emilio Bianchi, Imed-Eddine Gallouzi.
      Cachexia syndrome develops in patients with diseases such as cancer and sepsis and is characterized by progressive muscle wasting. While iNOS is one of the main effectors of cachexia, its mechanism of action and whether it could be targeted for therapy remains unexplored. Here, we show that iNOS knockout mice and mice treated with the clinically tested iNOS inhibitor GW274150 are protected against muscle wasting in models of both septic and cancer cachexia. We demonstrate that iNOS triggers muscle wasting by disrupting mitochondrial content, morphology, and energy production processes such as the TCA cycle and acylcarnitine transport. Notably, iNOS inhibits oxidative phosphorylation through impairment of complexes II and IV of the electron transport chain and reduces ATP production, leading to energetic stress, activation of AMPK, suppression of mTOR, and, ultimately, muscle atrophy. Importantly, all these effects were reversed by GW274150. Therefore, our data establish how iNOS induces muscle wasting under cachectic conditions and provide a proof of principle for the repurposing of iNOS inhibitors, such as GW274150 for the treatment of cachexia.
    Keywords:  cachexia; cancer; iNOS; inflammation; metabolism
    DOI:  https://doi.org/10.15252/emmm.202013591
  9. EMBO Mol Med. 2021 Jun 08. e14089
    Targeting the SHP2 phosphatase promotes vascular damage and inhibition of tumor growth.
    Yuyi Wang, Ombretta Salvucci, Hidetaka Ohnuki, Andy D Tran, Taekyu Ha, Jing-Xin Feng, Michael DiPrima, Hyeongil Kwak, Dunrui Wang, Yanlin Yu, Michael Kruhlak, Giovanna Tosato.
      The tyrosine phosphatase SHP2 is oncogenic in cancers driven by receptor-tyrosine-kinases, and SHP2 inhibition reduces tumor growth. Here, we report that SHP2 is an essential promoter of endothelial cell survival and growth in the remodeling tumor vasculature. Using genetic and chemical approaches to inhibit SHP2 activity in endothelial cells, we show that SHP2 inhibits pro-apoptotic STAT3 and stimulates proliferative ERK1/2 signaling. Systemic SHP2 inhibition in mice bearing tumor types selected for SHP2-independent tumor cell growth promotes degeneration of the tumor vasculature and blood extravasation; reduces tumor vascularity and blood perfusion; and increases tumor necrosis. Reduction of tumor growth ensues, independent of SHP2 targeting in the tumor cells, blocking immune checkpoints, or recruiting macrophages. We also show that inhibiting the Angiopoietin/TIE2/AKT cascade magnifies the vascular and anti-tumor effects of SHP2 inhibition by blocking tumor endothelial AKT signaling, not a target of SHP2. Since the SHP2 and Ang2/TIE2 pathways are active in vascular endothelial cells of human melanoma and colon carcinoma, SHP2 inhibitors alone or with Ang2/TIE2 inhibitors hold promise to effectively target the tumor endothelium.
    Keywords:  SHP2; cancer; endothelial cells; tumor growth; tumor vasculature
    DOI:  https://doi.org/10.15252/emmm.202114089
  10. Gastroenterology. 2021 Jun 02. pii: S0016-5085(21)03075-4. [Epub ahead of print]
    New insights into pancreatic cancer: notes from a virtual meeting.
    Elisabeth Hessmann, Günter Schneider, .
      Pancreatic ductal adenocarcinoma (PDAC) remains a major challenge in cancer medicine. Given the increase in incidence and mortality, interdisciplinary research is necessary to translate basic knowledge into therapeutic strategies improving the outcome of patients. On the 4th and 5th of February 2021, three German pancreatic cancer research centers, the clinical research unit (CRU) 5002 from Göttingen, the collaborative research center (CRC) 1321 from Munich, and CRU325 from Marburg organized the 1stVirtual Göttingen-Munich-Marburg Pancreatic Cancer Meeting in order to foster scientific exchange. This report summarizes current research and proceedings presented during the meeting.
    DOI:  https://doi.org/10.1053/j.gastro.2021.04.082
  11. Cell Rep. 2021 Jun 08. pii: S2211-1247(21)00562-3. [Epub ahead of print]35(10): 109212
    High-fat diet-activated fatty acid oxidation mediates intestinal stemness and tumorigenicity.
    Miyeko D Mana, Amanda M Hussey, Constantine N Tzouanas, Shinya Imada, Yesenia Barrera Millan, Dorukhan Bahceci, Dominic R Saiz, Anna T Webb, Caroline A Lewis, Peter Carmeliet, Maria M Mihaylova, Alex K Shalek, Ömer H Yilmaz.
      Obesity is an established risk factor for cancer in many tissues. In the mammalian intestine, a pro-obesity high-fat diet (HFD) promotes regeneration and tumorigenesis by enhancing intestinal stem cell (ISC) numbers, proliferation, and function. Although PPAR (peroxisome proliferator-activated receptor) nuclear receptor activity has been proposed to facilitate these effects, their exact role is unclear. Here we find that, in loss-of-function in vivo models, PPARα and PPARδ contribute to the HFD response in ISCs. Mechanistically, both PPARs do so by robustly inducing a downstream fatty acid oxidation (FAO) metabolic program. Pharmacologic and genetic disruption of CPT1A (the rate-controlling enzyme of mitochondrial FAO) blunts the HFD phenotype in ISCs. Furthermore, inhibition of CPT1A dampens the pro-tumorigenic consequences of a HFD on early tumor incidence and progression. These findings demonstrate that inhibition of a HFD-activated FAO program creates a therapeutic opportunity to counter the effects of a HFD on ISCs and intestinal tumorigenesis.
    Keywords:  Apc; Cpt1a; Ppar; fatty acid oxidation; high-fat diet; intestinal stem cells
    DOI:  https://doi.org/10.1016/j.celrep.2021.109212
  12. J Clin Transl Res. 2021 Apr 22. 7(2): 257-262
    Association of losartan with outcomes in metastatic pancreatic cancer patients treated with chemotherapy.
    Anup Kasi, Jessica Allen, Kathan Mehta, Prasad Dandawate, Subhrajit Saha, Stefan Bossmann, Shrikant Anant, Weijing Sun.
      Background: Previous trials have shown improved efficacy of neoadjuvant treatment when combined with angiotensin II receptor antagonist, losartan in patients with locally advanced pancreatic ductal adenocarcinoma (PDA). However, role of losartan is unknown in metastatic PDA. In this retrospective observational study, we examined the relationship between losartan use at time of diagnosis and continued through chemotherapy treatment with clinical outcomes in patients with metastatic PDA that received chemotherapy.Methods: We retrospectively evaluated 114 metastatic PDA patients treated at University of Kansas Cancer Center between January 2000 and November 2019. We compared overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) between patients using losartan at time of their cancer diagnosis and a control group of patients who were not on losartan. A subgroup analysis was performed based on patients who were on a 100 mg dose of losartan along with chemotherapy versus patients treated with chemotherapy (without losartan). Another subgroup analysis was performed based on chemotherapy regimen: Fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX) versus Gemcitabine and Abraxane.
    Results: No significant difference was found in OS (p=0.466) or PFS (p=0.919) in patients on losartan (median 274 day, 83 day) and control patients (median 279 day, 111 day). No significant difference was found in ORR (p=0.621) or in DCR (p=0.497). No significant difference was found in OS (p=0.771) or PFS (p=0.0604) in losartan patients (median 347 day, 350 day) and control patients (median 333 day, 101 day) treated with FOLFIRINOX. No significant difference was found in OS (p=0.916) or PFS (p=0.341) in losartan (median 312 day, 69 day) and control patients (median 221 day, 136 day) treated with Gemcitabine plus Abraxane. No significant difference was found in OS (p=0.727) or PFS (p=0.790) in 100 mg losartan patients (median 261 day, 84 day) and control (median 279 day, 111 day).
    Conclusions: Patients on losartan at time of diagnosis and continued through chemotherapy treatment had no significant difference in OS, PFS, ORR, DCR than control patients. Subgroup analysis of patients treated with FOLFIRINOX revealed a longer PFS with losartan than control but did not reach statistical significance, likely due to small sample size. Our findings should be validated in a larger cohort to confirm if the benefit of losartan and FOLFIRINOX seen in a neoadjuvant setting for locally advanced cancer also applies to metastatic cancer.
    Relevance for Patients: This research adds to growing data on the efficacy of angiotensin receptor blocking drugs as adjunctive treatment in addition to chemotherapy in pancreatic cancer with specific focus on metastatic disease.
    Keywords:  angiotensin II receptor antagonists; angiotensin receptor blockers; losartan; metastatic pancreatic cancer; pancreatic cancer
  13. Aging Cell. 2021 Jun 08. e13415
    Exercise reduces circulating biomarkers of cellular senescence in humans.
    Davis A Englund, Ayumi E Sakamoto, Chad M Fritsche, Amanda A Heeren, Xu Zhang, Brian R Kotajarvi, Denise R Lecy, Matthew J Yousefzadeh, Marissa J Schafer, Thomas A White, Elizabeth J Atkinson, Nathan K LeBrasseur.
      Cellular senescence has emerged as a significant and potentially tractable mechanism of aging and multiple aging-related conditions. Biomarkers of senescent cell burden, including molecular signals in circulating immune cells and the abundance of circulating senescence-related proteins, have been associated with chronological age and clinical parameters of biological age in humans. The extent to which senescence biomarkers are affected by interventions that enhance health and function has not yet been examined. Here, we report that a 12-week structured exercise program drives significant improvements in several performance-based and self-reported measures of physical function in older adults. Impressively, the expression of key markers of the senescence program, including p16, p21, cGAS, and TNFα, were significantly lowered in CD3+ T cells in response to the intervention, as were the circulating concentrations of multiple senescence-related proteins. Moreover, partial least squares discriminant analysis showed levels of senescence-related proteins at baseline were predictive of changes in physical function in response to the exercise intervention. Our study provides first-in-human evidence that biomarkers of senescent cell burden are significantly lowered by a structured exercise program and predictive of the adaptive response to exercise.
    Keywords:  aging; immune cells; inflammation; senotherapeutics
    DOI:  https://doi.org/10.1111/acel.13415
  14. EMBO Rep. 2021 Jun 08. e52032
    Aneuploid senescent cells activate NF-κB to promote their immune clearance by NK cells.
    Ruoxi W Wang, Sonia Viganò, Uri Ben-David, Angelika Amon, Stefano Santaguida.
      The immune system plays a major role in the protection against cancer. Identifying and characterizing the pathways mediating this immune surveillance are thus critical for understanding how cancer cells are recognized and eliminated. Aneuploidy is a hallmark of cancer, and we previously found that untransformed cells that had undergone senescence due to highly abnormal karyotypes are eliminated by natural killer (NK) cells in vitro. However, the mechanisms underlying this process remained elusive. Here, using an in vitro NK cell killing system, we show that non-cell-autonomous mechanisms in aneuploid cells predominantly mediate their clearance by NK cells. Our data indicate that in untransformed aneuploid cells, NF-κB signaling upregulation is central to elicit this immune response. Inactivating NF-κB abolishes NK cell-mediated clearance of untransformed aneuploid cells. In cancer cell lines, NF-κB upregulation also correlates with the degree of aneuploidy. However, such upregulation in cancer cells is not sufficient to trigger NK cell-mediated clearance, suggesting that additional mechanisms might be at play during cancer evolution to counteract NF-κB-mediated immunogenicity.
    Keywords:  NF-κB; aneuploidy; complex karyotypes; immune clearance; senescence
    DOI:  https://doi.org/10.15252/embr.202052032
  15. Nat Rev Cancer. 2021 Jun 08.
    Cancer stem cell-immune cell crosstalk in tumour progression.
    Defne Bayik, Justin D Lathia.
      Cellular heterogeneity and an immunosuppressive tumour microenvironment are independent yet synergistic drivers of tumour progression and underlie therapeutic resistance. Recent studies have highlighted the complex interaction between these cell-intrinsic and cell-extrinsic mechanisms. The reciprocal communication between cancer stem cells (CSCs) and infiltrating immune cell populations in the tumour microenvironment is a paradigm for these interactions. In this Perspective, we discuss the signalling programmes that simultaneously induce CSCs and reprogramme the immune response to facilitate tumour immune evasion, metastasis and recurrence. We further highlight biological factors that can impact the nature of CSC-immune cell communication. Finally, we discuss targeting opportunities for simultaneous regulation of the CSC niche and immunosurveillance.
    DOI:  https://doi.org/10.1038/s41568-021-00366-w
  16. FASEB J. 2021 Jul;35(7): e21714
    Cancer-induced muscle atrophy is determined by intrinsic muscle oxidative capacity.
    Christiano R R Alves, Eric J Eichelberger, Willian das Neves, Márcio A C Ribeiro, Luiz R G Bechara, Vanessa A Voltarelli, Ney R de Almeida, Lars Hagen, Animesh Sharma, Julio C B Ferreira, Kathryn J Swoboda, Geir Slupphaug, Patricia C Brum.
      We tested the hypothesis that cancer cachexia progression would induce oxidative post-translational modifications (Ox-PTMs) associated with skeletal muscle wasting, with different responses in muscles with the prevalence of glycolytic and oxidative fibers. We used cysteine-specific isotopic coded affinity tags (OxICAT) and gel-free mass spectrometry analysis to investigate the cysteine Ox-PTMs profile in the proteome of both plantaris (glycolytic) and soleus (oxidative) muscles in tumor-bearing and control rats. Histological analysis revealed muscle atrophy in type II fibers in plantaris muscle, with no changes in plantaris type I fibers and no differences in both soleus type I and II fibers in tumor-bearing rats when compared to healthy controls. Tumor progression altered the Ox-PTMs profile in both plantaris and soleus. However, pathway analysis including the differentially oxidized proteins revealed tricarboxylic acid cycle and oxidative phosphorylation as main affected pathways in plantaris muscle from tumor-bearing rats, while the same analysis did not show main metabolic pathways affected in the soleus muscle. In addition, cancer progression affected several metabolic parameters such as ATP levels and markers of oxidative stress associated with muscle atrophy in plantaris muscle, but not in soleus. However, isolated soleus from tumor-bearing rats had a reduced force production capacity when compared to controls. These novel findings demonstrate that tumor-bearing rats have severe muscle atrophy exclusively in glycolytic fibers. Cancer progression is associated with cysteine Ox-PTMs in the skeletal muscle, but these modifications affect different pathways in a glycolytic muscle compared to an oxidative muscle, indicating that intrinsic muscle oxidative capacity determines the response to cancer cachectic effects.
    Keywords:  aerobic metabolism; atrophy; cancer cachexia; fiber type; muscle wasting
    DOI:  https://doi.org/10.1096/fj.202100263R
  17. Aging Cell. 2021 Jun 07. e13408
    Mitochondrial mistranslation modulated by metabolic stress causes cardiovascular disease and reduced lifespan.
    Tara R Richman, Judith A Ermer, Stefan J Siira, Irina Kuznetsova, Christopher A Brosnan, Giulia Rossetti, Jessica Baker, Kara L Perks, Henrietta Cserne Szappanos, Helena M Viola, Nicola Gray, Mark Larance, Livia C Hool, Steven Zuryn, Oliver Rackham, Aleksandra Filipovska.
      Changes in the rate and fidelity of mitochondrial protein synthesis impact the metabolic and physiological roles of mitochondria. Here we explored how environmental stress in the form of a high-fat diet modulates mitochondrial translation and affects lifespan in mutant mice with error-prone (Mrps12ep / ep ) or hyper-accurate (Mrps12ha / ha ) mitochondrial ribosomes. Intriguingly, although both mutations are metabolically beneficial in reducing body weight, decreasing circulating insulin and increasing glucose tolerance during a high-fat diet, they manifest divergent (either deleterious or beneficial) outcomes in a tissue-specific manner. In two distinct organs that are commonly affected by the metabolic disease, the heart and the liver, Mrps12ep / ep mice were protected against heart defects but sensitive towards lipid accumulation in the liver, activating genes involved in steroid and amino acid metabolism. In contrast, enhanced translational accuracy in Mrps12ha / ha mice protected the liver from a high-fat diet through activation of liver proliferation programs, but enhanced the development of severe hypertrophic cardiomyopathy and led to reduced lifespan. These findings reflect the complex transcriptional and cell signalling responses that differ between post-mitotic (heart) and highly proliferative (liver) tissues. We show trade-offs between the rate and fidelity of mitochondrial protein synthesis dictate tissue-specific outcomes due to commonly encountered stressful environmental conditions or aging.
    Keywords:  ageing; metabolism; mitochondria; protein synthesis
    DOI:  https://doi.org/10.1111/acel.13408
  18. J Biol Chem. 2021 Apr 29. pii: S0021-9258(21)00525-1. [Epub ahead of print] 100736
    The mitochondrial NADH pool is involved in hydrogen sulfide signaling and stimulation of aerobic glycolysis.
    Victor Vitvitsky, Roshan Kumar, Marouane Libiad, Allison Maebius, Aaron Landry, Ruma Banerjee.
      Hydrogen sulfide is synthesized by enzymes involved in sulfur metabolism and oxidized via a dedicated mitochondrial pathway that intersects with the electron transport chain (ETC) at the level of complex III. Studies with H2S are challenging since it is volatile and also reacts with oxidized thiols in the culture medium, forming sulfane sulfur species. The half-life of exogenously added H2S to cultured cells is unknown. In this study, we first examined the half-life of exogenously added H2S to human colonic epithelial cells. In plate cultures, H2S disappeared with a t1/2 of 3-4 min at 37°C with a small fraction being trapped as sulfane sulfur species. In suspension cultures, the rate of abiotic loss of H2S was slower, and we demonstrated that sulfide stimulated aerobic glycolysis, which was sensitive to the mitochondrial but not the cytoplasmic NADH pool. Oxidation of mitochondrial NADH using the genetically encoded mito-LbNOX tool, blunted the cellular sensitivity to sulfide-stimulated aerobic glycolysis and enhanced its oxidation to thiosulfate. In contrast, sulfide did not affect flux through the oxidative pentose phosphate pathway or the TCA cycle. Knockdown of sulfide quinone oxidoreductase, which commits H2S to oxidation, sensitized cells to sulfide-stimulated aerobic glycolysis. Finally, we observed that sulfide decreased ATP levels in cells. The dual potential of H2S to activate oxidative phosphorylation at low concentrations, but inhibit it at high concentrations, suggests that it might play a role in tuning electron flux and therefore, cellular energy metabolism, particularly during cell proliferation.
    Keywords:  Hydrogen sulfide; aerobic glycolysis; electron transport chain; sulfide quinone oxidoreductase
    DOI:  https://doi.org/10.1016/j.jbc.2021.100736
  19. Nat Commun. 2021 06 08. 12(1): 3444
    PRMT5-mediated arginine methylation activates AKT kinase to govern tumorigenesis.
    Shasha Yin, Liu Liu, Charles Brobbey, Viswanathan Palanisamy, Lauren E Ball, Shaun K Olsen, Michael C Ostrowski, Wenjian Gan.
      AKT is involved in a number of key cellular processes including cell proliferation, apoptosis and metabolism. Hyperactivation of AKT is associated with many pathological conditions, particularly cancers. Emerging evidence indicates that arginine methylation is involved in modulating AKT signaling pathway. However, whether and how arginine methylation directly regulates AKT kinase activity remain unknown. Here we report that protein arginine methyltransferase 5 (PRMT5), but not other PRMTs, promotes AKT activation by catalyzing symmetric dimethylation of AKT1 at arginine 391 (R391). Mechanistically, AKT1-R391 methylation cooperates with phosphatidylinositol 3,4,5 trisphosphate (PIP3) to relieve the pleckstrin homology (PH)-in conformation, leading to AKT1 membrane translocation and subsequent activation by phosphoinositide-dependent kinase-1 (PDK1) and the mechanistic target of rapamycin complex 2 (mTORC2). As a result, deficiency in AKT1-R391 methylation significantly suppresses AKT1 kinase activity and tumorigenesis. Lastly, we show that PRMT5 inhibitor synergizes with AKT inhibitor or chemotherapeutic drugs to enhance cell death. Altogether, our study suggests that R391 methylation is an important step for AKT activation and its oncogenic function.
    DOI:  https://doi.org/10.1038/s41467-021-23833-2
  20. HPB (Oxford). 2021 May 19. pii: S1365-182X(21)00140-4. [Epub ahead of print]
    Preoperative serum ADAM12 levels as a stromal marker for overall survival and benefit of adjuvant therapy in patients with resected pancreatic and periampullary cancer.
    Marin Strijker, Fleur van der Sijde, Mustafa Suker, Marja A Boermeester, Bert A Bonsing, Marco J Bruno, Olivier R Busch, Michail Doukas, Casper H van Eijck, Arja Gerritsen, Bas Groot Koerkamp, Nadia Haj Mohammad, Jony van Hilst, Ignace H de Hingh, Jeanin E van Hooft, Misha D Luyer, I Quintus Molenaar, Joanne Verheij, Cynthia Waasdorp, Johanna W Wilmink, Marc G Besselink, Hanneke W van Laarhoven, Maarten F Bijlsma, .
      BACKGROUND: We evaluated the stroma marker A Disintegrin And Metalloprotease 12 (ADAM12) as a preoperative prognostic and treatment-predictive marker for overall survival (OS) in pancreatic ductal adenocarcinoma (PDAC) and periampullary cancers.METHODS: Materials were derived from the prospective nationwide Dutch Pancreas Biobank (2015-2017). We included patients who underwent resection because of PDAC/periampullary cancer or non-invasive IPMN (control group) and had a preoperative serum sample available. ADAM12 levels were dichotomized using a pre-defined cut-off (316 pg/mL). Univariable and multivariable Cox regression analyses (backward selection) were performed.
    RESULTS: Median ADAM12 levels were 161 (IQR 79-352) pg/mL in 215 PDAC and periampullary adenocarcinomas. High ADAM12 levels (>316 pg/mL) predicted poor OS in the total group of pancreatic and periampullary adenocarcinomas (P = 0.04), but not after adjustment. In distal cholangiocarcinoma (n = 33), high ADAM12 levels predicted poor OS in univariable analysis (P = 0.02), but not in PDAC (P = 0.63). PDAC patients (n = 135) with high ADAM12 levels benefited from adjuvant treatment (median OS 27 vs 14 months, P = 0.02), whereas those with low levels did not (21 vs 21 months, P = 0.87).
    CONCLUSION: High circulating ADAM12 levels, as a proxy for activated stroma, predict survival benefit from adjuvant chemotherapy in PDAC, requiring validation in future studies.
    DOI:  https://doi.org/10.1016/j.hpb.2021.05.001
  21. STAR Protoc. 2021 Jun 18. 2(2): 100549
    Measuring the effect of drug treatments on primary human CD8+ T cell activation and cytolytic potential.
    Helen Loo Yau, Daniel D De Carvalho.
      CD8+ T cells are key effector cells in adaptive immune responses against intracellular pathogens and cancer cells. Systemic drug treatments, like chemotherapy, may positively or negatively affect CD8+ T cell function. In this protocol, we describe robust and optimized ex vivo polyclonal activation and cell culture conditions to measure drug treatments' effects on primary human CD8+ T cell activation and cytolytic potential. We provide streamlined methods for measuring effector cytokines and activation markers of CD8+ T cells via flow cytometry. For complete details on the use and execution of this protocol, please refer to Loo Yau et al. (2021).
    Keywords:  Cell isolation; Cell-based Assays; Flow Cytometry/Mass Cytometry; Immunology; Molecular/Chemical Probes
    DOI:  https://doi.org/10.1016/j.xpro.2021.100549
  22. Nat Commun. 2021 06 07. 12(1): 3414
    Suppression of tumor-associated neutrophils by lorlatinib attenuates pancreatic cancer growth and improves treatment with immune checkpoint blockade.
    Sebastian R Nielsen, Jan E Strøbech, Edward R Horton, Rene Jackstadt, Anu Laitala, Marina C Bravo, Giorgia Maltese, Adina R D Jensen, Raphael Reuten, Maria Rafaeva, Saadia A Karim, Chang-Il Hwang, Luis Arnes, David A Tuveson, Owen J Sansom, Jennifer P Morton, Janine T Erler.
      Pancreatic ductal adenocarcinoma (PDAC) patients have a 5-year survival rate of only 8% largely due to late diagnosis and insufficient therapeutic options. Neutrophils are among the most abundant immune cell type within the PDAC tumor microenvironment (TME), and are associated with a poor clinical prognosis. However, despite recent advances in understanding neutrophil biology in cancer, therapies targeting tumor-associated neutrophils are lacking. Here, we demonstrate, using pre-clinical mouse models of PDAC, that lorlatinib attenuates PDAC progression by suppressing neutrophil development and mobilization, and by modulating tumor-promoting neutrophil functions within the TME. When combined, lorlatinib also improves the response to anti-PD-1 blockade resulting in more activated CD8 + T cells in PDAC tumors. In summary, this study identifies an effect of lorlatinib in modulating tumor-associated neutrophils, and demonstrates the potential of lorlatinib to treat PDAC.
    DOI:  https://doi.org/10.1038/s41467-021-23731-7
  23. Oncologist. 2021 Jun 08.
    Phase II Study of 5-Fluorouracil, Oxaliplatin plus Dasatinib (FOLFOX-D) in First-Line Metastatic Pancreatic Adenocarcinoma.
    Thomas J George, Azka Ali, Yu Wang, Ji-Hyun Lee, Alison M Ivey, David DeRemer, Karen C Daily, Carmen J Allegra, Steven J Hughes, Z Hugh Fan, Miles E Cameron, Andrew R Judge, Jose G Trevino.
      LESSONS LEARNED: Pre-clinical studies have demonstrated that Src inhibition through dasatinib synergistically enhances the anti-tumor effects of oxaliplatin. In this phase II, single arm study, FOLFOX-D in previously untreated patients with mPC only showed only modest clinical activity, with a PFS of 4 months and OS of 10.6 months. Continued investigation is ongoing to better understand the role of Src inhibition with concurrent 5-FU and oxaliplatin in a subset of exceptional responders.BACKGROUND: Src tyrosine kinase activity is overexpressed in many human cancers, including metastatic pancreatic cancer (mPC). Dasatinib is a potent inhibitor of Src family of tyrosine kinases. This study was designed to investigate whether dasatinib can synergistically enhance anti-tumor effects of FOLFOX regimen (FOLFOX-D).
    METHODS: In this single arm, phase II study, previously untreated patients received dasatinib 150 mg oral daily on days 1-14, oxaliplatin 85 mg/m2 IV on day 1 every 14 days, leucovorin (LV) 400 mg/m2 IV on day 1 every 14 days, 5-fluorouracil (5FU) bolus 400 mg/m2 on day 1 every 14 days, and 5-FU continuous infusion 2,400 mg/m2 on day 1 every 14 days. Primary endpoint was progression-free survival (PFS) with pre-planned comparison to historical controls.
    RESULTS: Forty-four patients enrolled with an estimated median PFS of 4.0 (95% CI: 2.3-8.5) months, and overall survival (OS) of 10.6 (95% CI: 6.9-12.7) months. Overall response rate (ORR) was 22.7% (n=10): 1 patient (2.3%) with complete response (CR), and 9 patients (20.5%) with partial response. Fifteen patients (34.1%) had stable disease (SD). Nausea was the most common adverse event (AE) seen in 35 patients (79.5%).
    CONCLUSION: The addition of dasatinib did not appear to add incremental clinical benefit to FOLFOX in untreated mPC patients.
    Keywords:  Dasatinib; FOLFOX; Metastatic pancreatic cancer; Src
    DOI:  https://doi.org/10.1002/onco.13853
  24. Nat Commun. 2021 06 09. 12(1): 3486
    Regulation of the one carbon folate cycle as a shared metabolic signature of longevity.
    Andrea Annibal, Rebecca George Tharyan, Maribel Fides Schonewolff, Hannah Tam, Christian Latza, Markus Max Karl Auler, Adam Antebi.
      The metabolome represents a complex network of biological events that reflects the physiologic state of the organism in health and disease. Additionally, specific metabolites and metabolic signaling pathways have been shown to modulate animal ageing, but whether there are convergent mechanisms uniting these processes remains elusive. Here, we used high resolution mass spectrometry to obtain the metabolomic profiles of canonical longevity pathways in C. elegans to identify metabolites regulating life span. By leveraging the metabolomic profiles across pathways, we found that one carbon metabolism and the folate cycle are pervasively regulated in common. We observed similar changes in long-lived mouse models of reduced insulin/IGF signaling. Genetic manipulation of pathway enzymes and supplementation with one carbon metabolites in C. elegans reveal that regulation of the folate cycle represents a shared causal mechanism of longevity and proteoprotection. Such interventions impact the methionine cycle, and reveal methionine restriction as an underlying mechanism. This comparative approach reveals key metabolic nodes to enhance healthy ageing.
    DOI:  https://doi.org/10.1038/s41467-021-23856-9
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