bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2024–01–07
seventeen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Metabolic reprogramming in the tumor microenvironment: unleashing T cell stemness for enhanced cancer immunotherapy.
  2. T Cell Exhaustion.
  3. Transgelin 2 guards T cell lipid metabolic programming and anti-tumor function.
  4. Histone Deacetylase Inhibitors Directly Modulate T Cell Gene Expression and Signaling and Promote Development of Effector-Exhausted T Cells in Murine Tumors.
  5. IL-10-expressing CAR T cells resist dysfunction and mediate durable clearance of solid tumors and metastases.
  6. Fasting-activated ventrolateral medulla neurons regulate T cell homing and suppress autoimmune disease in mice.
  7. Author Correction: Apoptotic stress causes mtDNA release during senescence and drives the SASP.
  8. CD4+ T cell immunity is dependent on an intrinsic stem-like program.
  9. Metabolic regulation of γδ intraepithelial lymphocytes.
  10. Mitochondrial isocitrate dehydrogenase impedes CAR T cell function by restraining antioxidant metabolism and histone acetylation.
  11. Massively parallel base editing screens to map variant effects on anti-tumor hallmarks of primary human T cells.
  12. Multiple omics analysis reveals the regulation of SIRT5 on mitochondrial function and lipid metabolism during the differentiation of bovine preadipocytes.
  13. Copper overload induces apoptosis and impaired proliferation of T cell in zebrafish.
  14. Transcriptional and epigenetic dysregulation impairs generation of proliferative neural stem and progenitor cells during brain aging.
  15. Blocking methionine catabolism induces senescence and confers vulnerability to GSK3 inhibition in liver cancer.
  16. Longevity interventions modulate mechanotransduction and extracellular matrix homeostasis in C. elegans.
  17. Epigenetic checkpoints regulate the fate and function of CAR-T cells.
  1. Front Pharmacol. 2023 ;14 1327717
    Metabolic reprogramming in the tumor microenvironment: unleashing T cell stemness for enhanced cancer immunotherapy.
    Youhan Liu, Tao Wang, Wen Ma, Zixuan Jia, Qinglu Wang, Maoling Zhang, Ying Luo, Hongmei Sun.
      T cells play a pivotal role in the immune system by distinguishing between various harmful pathogens and cancerous cells within the human body and initiating an immune response. Within the tumor microenvironment (TME), immune effector T cells encounter both immunosuppressive cells and factors that hinder their functionality. Additionally, they endure robust and persistent antigenic stimulation, often leading to exhaustion and apoptosis. However, the stemness of T cells, characterized by their ability to survive and self-renew over extended periods, represents a primary target in immune checkpoint therapies such as anti-PD-1 therapy. T cell stemness encompasses specific memory T cell subsets and progenitor-exhausted T cells with stem cell-like properties. Therefore, understanding the impact of the TME on T cell stemness, including factors like K+, lactate, and H+, holds significant importance and can facilitate the mitigation of terminal T-cell depletion, the identification of potential resilient biomarkers or therapeutic targets resistant to immune checkpoint therapies, and ultimately lead to sustained anti-tumor effects. Thus, it offers a novel perspective for advancing tumor immunotherapy.
    Keywords:  H+; K+; cancer; lactate; tumor microenvironment
    DOI:  https://doi.org/10.3389/fphar.2023.1327717
  2. Annu Rev Immunol. 2024 Jan 02.
    T Cell Exhaustion.
    Andrew Baessler, Dario A A Vignali.
      T cell responses must be balanced to ensure adequate protection against malignant transformation and an array of pathogens while also limiting damage to healthy cells and preventing autoimmunity. T cell exhaustion serves as a regulatory mechanism to limit the activity and effector function of T cells undergoing chronic antigen stimulation. Exhausted T cells exhibit poor proliferative potential; high inhibitory receptor expression; altered transcriptome, epigenome, and metabolism; and, most importantly, reduced effector function. While exhaustion helps to restrain damage caused by aberrant T cells in settings of autoimmune disease, it also limits the ability of cells to respond against persistent infection and cancer, leading to disease progression. Here we review the process of T cell exhaustion, detailing the key characteristics and drivers as well as highlighting our current understanding of the underlying transcriptional and epigenetic programming. We also discuss how exhaustion can be targeted to enhance T cell functionality in cancer. Expected final online publication date for the Annual Review of Immunology, Volume 42 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-immunol-090222-110914
  3. Res Sq. 2023 Dec 14. pii: rs.3.rs-3683989. [Epub ahead of print]
    Transgelin 2 guards T cell lipid metabolic programming and anti-tumor function.
    Sung-Min Hwang, Deepika Awasthi, Jieun Jeong, Tito Sandoval, Chang-Suk Chae, Yusibeska Ramos, Chen Tan, Matias Marin Falco, Ian McBain, Bikash Mishra, Lionel B Ivashkiv, Dmitriy Zamarin, Evelyn Cantillo, Eloise Chapman-Davis, Kevin Holcomb, Diana Morales, Paulo Rodriguez, Jose Conejo-Garcia, Martin Kaczocha, Anna Vähärautio, Minkyung Song, Juan Cubillos-Ruiz.
      Mounting effective immunity against pathogens and tumors relies on the successful metabolic programming of T cells by extracellular fatty acids 1-3 . During this process, fatty-acid-binding protein 5 (FABP5) imports lipids that fuel mitochondrial respiration and sustain the bioenergetic requirements of protective CD8 + T cells 4,5 . Importantly, however, the mechanisms governing this crucial immunometabolic axis remain unexplored. Here we report that the cytoskeletal organizer Transgelin 2 (TAGLN2) is necessary for optimal CD8 + T cell fatty acid uptake, mitochondrial respiration, and anti-cancer function. We found that TAGLN2 interacts with FABP5, enabling the surface localization of this lipid importer on activated CD8 + T cells. Analysis of ovarian cancer specimens revealed that endoplasmic reticulum (ER) stress responses elicited by the tumor microenvironment repress TAGLN2 in infiltrating CD8 + T cells, enforcing their dysfunctional state. Restoring TAGLN2 expression in ER-stressed CD8 + T cells bolstered their lipid uptake, mitochondrial respiration, and cytotoxic capacity. Accordingly, chimeric antigen receptor T cells overexpressing TAGLN2 bypassed the detrimental effects of tumor-induced ER stress and demonstrated superior therapeutic efficacy in mice with metastatic ovarian cancer. Our study unveils the role of cytoskeletal TAGLN2 in T cell lipid metabolism and highlights the potential to enhance cellular immunotherapy in solid malignancies by preserving the TAGLN2-FABP5 axis.
    DOI:  https://doi.org/10.21203/rs.3.rs-3683989/v1
  4. J Immunol. 2024 Jan 03. pii: ji2300475. [Epub ahead of print]
    Histone Deacetylase Inhibitors Directly Modulate T Cell Gene Expression and Signaling and Promote Development of Effector-Exhausted T Cells in Murine Tumors.
    Mohammed L Ibrahim, Hong Zheng, Margaret L Barlow, Yousuf Latif, Zhihua Chen, Xiaoqing Yu, Amer A Beg.
      Epigenetic regulation plays a crucial role in the development and progression of cancer, including the regulation of antitumor immunity. The reversible nature of epigenetic modifications offers potential therapeutic avenues for cancer treatment. In particular, histone deacetylase (HDAC) inhibitors (HDACis) have been shown to promote antitumor T cell immunity by regulating myeloid cell types, enhancing tumor Ag presentation, and increasing expression of chemokines. HDACis are currently being evaluated to determine whether they can increase the response rate of immune checkpoint inhibitors in cancer patients. Although the potential direct effect of HDACis on T cells likely impacts antitumor immunity, little is known about how HDAC inhibition alters the transcriptomic profile of T cells. In this article, we show that two clinical-stage HDACis profoundly impact gene expression and signaling networks in CD8+ and CD4+ T cells. Specifically, HDACis promoted T cell effector function by enhancing expression of TNF-α and IFN-γ and increasing CD8+ T cell cytotoxicity. Consistently, in a murine tumor model, HDACis led to enrichment of CD8+ T cell subsets with high expression of effector molecules (Prf1, Ifng, Gzmk, and Grmb) but also molecules associated with T cell exhaustion (Tox, Pdcd1, Lag3, and Havcr2). HDACis further generated a tumor microenvironment dominated by myeloid cells with immune suppressive signatures. These results indicate that HDACis directly and favorably augment T cell effector function but also increase their exhaustion signal in the tumor microenvironment, which may add a layer of complexity for achieving clinical benefit in combination with immune checkpoint inhibitors.
    DOI:  https://doi.org/10.4049/jimmunol.2300475
  5. Nat Biotechnol. 2024 Jan 02.
    IL-10-expressing CAR T cells resist dysfunction and mediate durable clearance of solid tumors and metastases.
    Yang Zhao, Jiangqing Chen, Massimo Andreatta, Bing Feng, Yu-Qing Xie, Mathias Wenes, Yi Wang, Min Gao, Xiaomeng Hu, Pedro Romero, Santiago Carmona, Jie Sun, Yugang Guo, Li Tang.
      The success of chimeric antigen receptor (CAR) T cell therapy in treating several hematopoietic malignancies has been difficult to replicate in solid tumors, in part because of T cell exhaustion and eventually dysfunction. To counter T cell dysfunction in the tumor microenvironment, we metabolically armored CAR T cells by engineering them to secrete interleukin-10 (IL-10). We show that IL-10 CAR T cells preserve intact mitochondrial structure and function in the tumor microenvironment and increase oxidative phosphorylation in a mitochondrial pyruvate carrier-dependent manner. IL-10 secretion promoted proliferation and effector function of CAR T cells, leading to complete regression of established solid tumors and metastatic cancers across several cancer types in syngeneic and xenograft mouse models, including colon cancer, breast cancer, melanoma and pancreatic cancer. IL-10 CAR T cells also induced stem cell-like memory responses in lymphoid organs that imparted durable protection against tumor rechallenge. Our results establish a generalizable approach to counter CAR T cell dysfunction through metabolic armoring, leading to solid tumor eradication and long-lasting immune protection.
    DOI:  https://doi.org/10.1038/s41587-023-02060-8
  6. Nat Neurosci. 2024 Jan 05.
    Fasting-activated ventrolateral medulla neurons regulate T cell homing and suppress autoimmune disease in mice.
    Liang Wang, Mingxiu Cheng, Yuchen Wang, Jing Chen, Famin Xie, Li-Hao Huang, Cheng Zhan.
      Dietary fasting markedly influences the distribution and function of immune cells and exerts potent immunosuppressive effects. However, the mechanisms through which fasting regulates immunity remain obscure. Here we report that catecholaminergic (CA) neurons in the ventrolateral medulla (VLM) are activated during fasting in mice, and we demonstrate that the activity of these CA neurons impacts the distribution of T cells and the development of autoimmune disease in an experimental autoimmune encephalomyelitis (EAE) model. Ablation of VLM CA neurons largely reversed fasting-mediated T cell redistribution. Activation of these neurons drove T cell homing to bone marrow in a CXCR4/CXCL12 axis-dependent manner, which may be mediated by a neural circuit that stimulates corticosterone secretion. Similar to fasting, the continuous activation of VLM CA neurons suppressed T cell activation, proliferation, differentiation and cytokine production in autoimmune mouse models and substantially alleviated disease symptoms. Collectively, our study demonstrates neuronal control of inflammation and T cell distribution, suggesting a neural mechanism underlying fasting-mediated immune regulation.
    DOI:  https://doi.org/10.1038/s41593-023-01543-w
  7. Nature. 2024 Jan 02.
    Author Correction: Apoptotic stress causes mtDNA release during senescence and drives the SASP.
    Stella Victorelli, Hanna Salmonowicz, James Chapman, Helene Martini, Maria Grazia Vizioli, Joel S Riley, Catherine Cloix, Ella Hall-Younger, Jair Machado Espindola-Netto, Diana Jurk, Anthony B Lagnado, Lilian Sales Gomez, Joshua N Farr, Dominik Saul, Rebecca Reed, George Kelly, Madeline Eppard, Laura C Greaves, Zhixun Dou, Nicholas Pirius, Karolina Szczepanowska, Rebecca A Porritt, Huijie Huang, Timothy Y Huang, Derek A Mann, Claudio Akio Masuda, Sundeep Khosla, Haiming Dai, Scott H Kaufmann, Emmanouil Zacharioudakis, Evripidis Gavathiotis, Nathan K LeBrasseur, Xue Lei, Alva G Sainz, Viktor I Korolchuk, Peter D Adams, Gerald S Shadel, Stephen W G Tait, João F Passos.
      
    DOI:  https://doi.org/10.1038/s41586-023-07002-7
  8. Nat Immunol. 2024 Jan;25(1): 66-76
    CD4+ T cell immunity is dependent on an intrinsic stem-like program.
    Dawei Zou, Zheng Yin, Stephanie G Yi, Guohua Wang, Yang Guo, Xiang Xiao, Shuang Li, Xiaolong Zhang, Nancy M Gonzalez, Laurie J Minze, Lin Wang, Stephen T C Wong, A Osama Gaber, Rafik M Ghobrial, Xian C Li, Wenhao Chen.
      CD4+ T cells are central to various immune responses, but the molecular programs that drive and maintain CD4+ T cell immunity are not entirely clear. Here we identify a stem-like program that governs the CD4+ T cell response in transplantation models. Single-cell-transcriptomic analysis revealed that naive alloantigen-specific CD4+ T cells develop into TCF1hi effector precursor (TEP) cells and TCF1-CXCR6+ effectors in transplant recipients. The TCF1-CXCR6+CD4+ effectors lose proliferation capacity and do not reject allografts upon adoptive transfer into secondary hosts. By contrast, the TCF1hiCD4+ TEP cells have dual features of self-renewal and effector differentiation potential, and allograft rejection depends on continuous replenishment of TCF1-CXCR6+ effectors from TCF1hiCD4+ TEP cells. Mechanistically, TCF1 sustains the CD4+ TEP cell population, whereas the transcription factor IRF4 and the glycolytic enzyme LDHA govern the effector differentiation potential of CD4+ TEP cells. Deletion of IRF4 or LDHA in T cells induces transplant acceptance. These findings unravel a stem-like program that controls the self-renewal capacity and effector differentiation potential of CD4+ TEP cells and have implications for T cell-related immunotherapies.
    DOI:  https://doi.org/10.1038/s41590-023-01682-z
  9. Discov Immunol. 2023 ;pii: kyad011. [Epub ahead of print]2(1):
    Metabolic regulation of γδ intraepithelial lymphocytes.
    Sara Alonso, Karen Edelblum.
      Elucidating the relationship between cellular metabolism and T cell function has substantially advanced our understanding of how T cells are regulated in response to activation. The metabolic profiles of circulating or peripheral T cells have been well-described, yet less is known regarding how complex local microenvironments shape or modulate the bioenergetic profile of tissue-resident T lymphocytes. Intraepithelial lymphocytes expressing the γδ T cell receptor (γδ IEL) provide immunosurveillance of the intestinal epithelium to limit tissue injury and microbial invasion; however, their activation and effector responses occur independently of antigen recognition. In this review, we will summarize the current knowledge regarding γδ T cell and IEL metabolic profiles and how this informs our understanding of γδ IEL metabolism. We will also discuss the role of the gut microbiota in shaping the metabolic profile of these sentinel lymphocytes, and in turn, how these bioenergetics contribute to regulation of γδ IEL surveillance behavior and effector function. Improved understanding of the metabolic processes involved in γδ IEL homeostasis and function may yield novel strategies to amplify the protective functions of these cells in the context of intestinal health and disease.
    Keywords:  immunometabolism; intestine; intraepithelial lymphocytes; γδ T cells
    DOI:  https://doi.org/10.1093/discim/kyad011
  10. Cell Metab. 2024 Jan 02. pii: S1550-4131(23)00461-8. [Epub ahead of print]36(1): 176-192.e10
    Mitochondrial isocitrate dehydrogenase impedes CAR T cell function by restraining antioxidant metabolism and histone acetylation.
    Xiaohui Si, Mi Shao, Xinyi Teng, Yue Huang, Ye Meng, Longyuan Wu, Jieping Wei, Lianxuan Liu, Tianning Gu, Junzhe Song, Ruirui Jing, Xingyuan Zhai, Xin Guo, Delin Kong, Xiujian Wang, Bohan Cai, Ying Shen, Zhaoru Zhang, Dongrui Wang, Yongxian Hu, Pengxu Qian, Gang Xiao, He Huang.
      The efficacy of chimeric antigen receptor (CAR) T cell therapy is hampered by relapse in hematologic malignancies and by hyporesponsiveness in solid tumors. Long-lived memory CAR T cells are critical for improving tumor clearance and long-term protection. However, during rapid ex vivo expansion or in vivo tumor eradication, metabolic shifts and inhibitory signals lead to terminal differentiation and exhaustion of CAR T cells. Through a mitochondria-related compound screening, we find that the FDA-approved isocitrate dehydrogenase 2 (IDH2) inhibitor enasidenib enhances memory CAR T cell formation and sustains anti-leukemic cytotoxicity in vivo. Mechanistically, IDH2 impedes metabolic fitness of CAR T cells by restraining glucose utilization via the pentose phosphate pathway, which alleviates oxidative stress, particularly in nutrient-restricted conditions. In addition, IDH2 limits cytosolic acetyl-CoA levels to prevent histone acetylation that promotes memory cell formation. In combination with pharmacological IDH2 inhibition, CAR T cell therapy is demonstrated to have superior efficacy in a pre-clinical model.
    Keywords:  chimeric antigen receptor T cell; enasidenib; exhaustion; histone acetylation; isocitrate dehydrogenase 2; memory T cell formation; nutrient-restricted conditions; pentose phosphate pathway
    DOI:  https://doi.org/10.1016/j.cmet.2023.12.010
  11. bioRxiv. 2023 Dec 14. pii: 2023.12.13.571465. [Epub ahead of print]
    Massively parallel base editing screens to map variant effects on anti-tumor hallmarks of primary human T cells.
    Zachary H Walsh, Parin Shah, Neeharika Kothapalli, Gergo Nikolenyi, Shivem B Shah, Giuseppe Leuzzi, Michael Mu, Patricia Ho, Sinan Abuzaid, Zack D Brodtman, Neil Vasan, Mohammed AlQuraishi, Joshua D Milner, Alberto Ciccia, Johannes C Melms, Benjamin Izar.
      Base editing enables generation of single nucleotide variants, but large-scale screening in primary human T cells is limited due to low editing efficiency, among other challenges 1 . Here, we developed a high-throughput approach for high-efficiency and massively parallel adenine and cytosine base-editor screening in primary human T cells. We performed multiple large-scale screens editing 102 genes with central functions in T cells and full-length tiling mutagenesis of selected genes, and read out variant effects on hallmarks of T cell anti-tumor immunity, including activation, proliferation, and cytokine production. We discovered a broad landscape of gain- and loss-of-function mutations, including in PIK3CD and its regulatory subunit encoded by PIK3R1, LCK , AKT1, CTLA-4 and JAK1 . We identified variants that affected several (e.g., PIK3CD C416R) or only selected (e.g. LCK Y505C) hallmarks of T cell activity, and functionally validated several hits by probing downstream signaling nodes and testing their impact on T cell polyfunctionality and proliferation. Using primary human T cells in which we engineered a T cell receptor (TCR) specific to a commonly presented tumor testis antigen as a model for cellular immunotherapy, we demonstrate that base edits identified in our screens can tune specific or broad T cell functions and ultimately improve tumor elimination while exerting minimal off-target activity. In summary, we present the first large-scale base editing screen in primary human T cells and provide a framework for scalable and targeted base editing at high efficiency. Coupled with multi-modal phenotypic mapping, we accurately nominate variants that produce a desirable T cell state and leverage these synthetic proteins to improve models of cellular cancer immunotherapies.
    DOI:  https://doi.org/10.1101/2023.12.13.571465
  12. Genomics. 2023 Dec 27. pii: S0888-7543(23)00217-3. [Epub ahead of print]116(1): 110773
    Multiple omics analysis reveals the regulation of SIRT5 on mitochondrial function and lipid metabolism during the differentiation of bovine preadipocytes.
    Jieyun Hong, Sayed Haidar Abbas Raza, Hongming Ma, Weina Cao, Yuqing Chong, Jiao Wu, Dongmei Xi, Weidong Deng.
      Preadipocyte differentiation represents a critical stage in adipogenesis, with mitochondria playing an undeniable pivotal role. Given the intricate interplay between transcription and metabolic signaling during adipogenesis, the regulation of sirtuin 5 (SIRT5) on mitochondrial function and lipid metabolism was revealed via multiple omics analysis. The findings suggest that SIRT5 plays a crucial role in promoting mitochondrial biosynthesis and maintaining mitochondrial function during preadipocyte differentiation. Moreover, SIRT5 modulates the metabolic levels of numerous bioactive substances by extensively regulating genes expression associated with differentiation, energy metabolism, lipid synthesis, and mitochondrial function. Finally, SIRT5 was found to suppress triacylglycerols (TAG) accumulation while enhancing the proportion and diversity of unsaturated fatty acids, and providing conditions for the expansion and stability of membrane structure during mitochondrial biosynthesis through numerous gene regulations. Our findings provide a foundation for the identification of crucial functional genes, signaling pathways, and metabolic substances associated with adipose tissue differentiation and metabolism.
    Keywords:  Bovine; Lipid metabolism; Mitochondrial function; Multiple omics analysis; Preadipocyte differentiation; SIRT5
    DOI:  https://doi.org/10.1016/j.ygeno.2023.110773
  13. Aquat Toxicol. 2023 Dec 19. pii: S0166-445X(23)00410-1. [Epub ahead of print]267 106808
    Copper overload induces apoptosis and impaired proliferation of T cell in zebrafish.
    LingYa Li, JiaHao Shi, WenYe Liu, Yi Luo, Sheng Gao, Jing-Xia Liu.
      Copper is an essential biometal for cell development and function, however, unbalanced copper homeostasis in T cell development and the underlying mechanisms are largely unexplored. Here, we use a zebrafish model to investigate the effect of copper overload in T cell development. We show that copper stressed zebrafish larvae exhibit a significant reduction in T cells with increased cell apoptosis and impaired cell proliferation. T cell progenitors, hematopoietic stem and progenitor cells, also exhibit increased cell apoptosis. Copper overload induces production of ROS and the down-regulations of its resistance genes foxos, and ectopic expression of foxo3a, ROS scavenger GSH, could both effectively rescue the reduction of T cells in copper overload larvae. Moreover, foxm1-cytoskeleton axis, parallel to ROS-foxo axis, also mediates the copper overload induced T cell developmental defects. Meanwhile, ROS destroys expression of cytoskeleton rather than of foxm1 in the cells to induce cell apoptosis and the impaired proliferation. The functional integrity of copper transporters cox17 and atp7b are required for copper stress in inducing T cell apoptosis and proliferation impairment. Our findings demonstrate that the down-stream ROS-foxo/cytoskeleton and foxm1-cytoskeleton signaling pathways contribute jointly to copper overload induced T cell apoptosis and proliferation defects, which are depend on the integral function of Cox17 and Atp7b, and provide new insight into the copper homeostasis in T lymphocyte development.
    Keywords:  Apoptosis; Foxm1-cytoskeleton; Proliferation; ROS-foxo; T cell
    DOI:  https://doi.org/10.1016/j.aquatox.2023.106808
  14. Nat Aging. 2024 Jan 04.
    Transcriptional and epigenetic dysregulation impairs generation of proliferative neural stem and progenitor cells during brain aging.
    Meiyang Li, Hongzhi Guo, Michael Carey, Chengyang Huang.
      The decline in stem cell function during aging may affect the regenerative capacity of mammalian organisms; however, the gene regulatory mechanism underlying this decline remains unclear. Here we show that the aging of neural stem and progenitor cells (NSPCs) in the male mouse brain is characterized by a decrease in the generation efficacy of proliferative NSPCs rather than the changes in lineage specificity of NSPCs. We reveal that the downregulation of age-dependent genes in NSPCs drives cell aging by decreasing the population of actively proliferating NSPCs while increasing the expression of quiescence markers. We found that epigenetic deregulation of the MLL complex at promoters leads to transcriptional inactivation of age-dependent genes, highlighting the importance of the dynamic interaction between histone modifiers and gene regulatory elements in regulating transcriptional program of aging cells. Our study sheds light on the key intrinsic mechanisms driving stem cell aging through epigenetic regulators and identifies potential rejuvenation targets that could restore the function of aging stem cells.
    DOI:  https://doi.org/10.1038/s43587-023-00549-0
  15. Nat Cancer. 2024 Jan 02.
    Blocking methionine catabolism induces senescence and confers vulnerability to GSK3 inhibition in liver cancer.
    Fuming Li, Pingyu Liu, Wen Mi, Liucheng Li, Nicole M Anderson, Nicholas P Lesner, Michelle Burrows, Jacqueline Plesset, Ariana Majer, Guanlin Wang, Jinyang Li, Lingzhi Zhu, Brian Keith, M Celeste Simon.
      Availability of the essential amino acid methionine affects cellular metabolism and growth, and dietary methionine restriction has been implicated as a cancer therapeutic strategy. Nevertheless, how liver cancer cells respond to methionine deprivation and underlying mechanisms remain unclear. Here we find that human liver cancer cells undergo irreversible cell cycle arrest upon methionine deprivation in vitro. Blocking methionine adenosyl transferase 2A (MAT2A)-dependent methionine catabolism induces cell cycle arrest and DNA damage in liver cancer cells, resulting in cellular senescence. A pharmacological screen further identified GSK3 inhibitors as senolytics that selectively kill MAT2A-inhibited senescent liver cancer cells. Importantly, combined treatment with MAT2A and GSK3 inhibitors therapeutically blunts liver tumor growth in vitro and in vivo across multiple models. Together, methionine catabolism is essential for liver tumor growth, and its inhibition can be exploited as an improved pro-senescence strategy for combination with senolytic agents to treat liver cancer.
    DOI:  https://doi.org/10.1038/s43018-023-00671-3
  16. Nat Commun. 2024 Jan 04. 15(1): 276
    Longevity interventions modulate mechanotransduction and extracellular matrix homeostasis in C. elegans.
    Alina C Teuscher, Cyril Statzer, Anita Goyala, Seraina A Domenig, Ingmar Schoen, Max Hess, Alexander M Hofer, Andrea Fossati, Viola Vogel, Orcun Goksel, Ruedi Aebersold, Collin Y Ewald.
      Dysfunctional extracellular matrices (ECM) contribute to aging and disease. Repairing dysfunctional ECM could potentially prevent age-related pathologies. Interventions promoting longevity also impact ECM gene expression. However, the role of ECM composition changes in healthy aging remains unclear. Here we perform proteomics and in-vivo monitoring to systematically investigate ECM composition (matreotype) during aging in C. elegans revealing three distinct collagen dynamics. Longevity interventions slow age-related collagen stiffening and prolong the expression of collagens that are turned over. These prolonged collagen dynamics are mediated by a mechanical feedback loop of hemidesmosome-containing structures that span from the exoskeletal ECM through the hypodermis, basement membrane ECM, to the muscles, coupling mechanical forces to adjust ECM gene expression and longevity via the transcriptional co-activator YAP-1 across tissues. Our results provide in-vivo evidence that coordinated ECM remodeling through mechanotransduction is required and sufficient to promote longevity, offering potential avenues for interventions targeting ECM dynamics.
    DOI:  https://doi.org/10.1038/s41467-023-44409-2
  17. Nat Immunol. 2024 Jan;25(1): 4-6
    Epigenetic checkpoints regulate the fate and function of CAR-T cells.
    Monica Casucci, Chiara Bonini, Eliana Ruggiero.
      
    DOI:  https://doi.org/10.1038/s41590-023-01708-6
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