bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2023‒01‒15
nine papers selected by
Linda Chan
Cleveland Clinic
  1. Microenvironment-driven metabolic adaptations guiding CD8+ T cell anti-tumor immunity.
  2. Tumor-intrinsic IRE1α signaling controls protective immunity in lung cancer.
  3. Arginine limitation drives a directed codon-dependent DNA sequence evolution response in colorectal cancer cells.
  4. Cell-cell metabolite exchange creates a pro-survival metabolic environment that extends lifespan.
  5. Metabolism in stem cell driven leukaemia: parallels between haematopoiesis and immunity.
  6. GOT1 regulates CD8+ effector and memory T cell generation.
  7. Intersection of immune and oncometabolic pathways drives cancer hyperprogression during immunotherapy.
  8. OGT controls mammalian cell viability by regulating the proteasome/mTOR/ mitochondrial axis.
  9. A central role for regulated protein stability in the control of TFE3 and MITF by nutrients.
  1. Immunity. 2023 Jan 10. pii: S1074-7613(22)00644-6. [Epub ahead of print]56(1): 32-42
    Microenvironment-driven metabolic adaptations guiding CD8+ T cell anti-tumor immunity.
    Jaeoh Park, Pei-Chun Hsueh, Zhiyu Li, Ping-Chih Ho.
      The metabolic stress occurring in the tumor microenvironment (TME) hampers T cell anti-tumor immunity by disturbing T cell metabolic and epigenetic programs. Recent studies are making headway toward identifying strategies to unleash T cell activities by targeting T cell metabolism. Furthermore, efforts have been made to improve the efficacy of immune checkpoint blockade and adoptive cell transfer therapies. However, distinct treatment outcomes across different cancers raise the question of whether our understanding of the features of CD8+ T cells within the TME are universal, regardless of their tissue of origin. Here, we review the common and distinct environmental factors affecting CD8+ T cells across tumors. Moreover, we discuss how distinct tissue-specific niches are interpreted by CD8+ T cells based on studies on tissue-resident memory T (Trm) cells and how these insights can pave the way for a better understanding of the metabolic regulation of CD8+ T cell differentiation and anti-tumor immunity.
    DOI:  https://doi.org/10.1016/j.immuni.2022.12.008
  2. Nat Commun. 2023 Jan 09. 14(1): 120
    Tumor-intrinsic IRE1α signaling controls protective immunity in lung cancer.
    Michael J P Crowley, Bhavneet Bhinder, Geoffrey J Markowitz, Mitchell Martin, Akanksha Verma, Tito A Sandoval, Chang-Suk Chae, Shira Yomtoubian, Yang Hu, Sahil Chopra, Diamile A Tavarez, Paolo Giovanelli, Dingcheng Gao, Timothy E McGraw, Nasser K Altorki, Olivier Elemento, Juan R Cubillos-Ruiz, Vivek Mittal.
      IRE1α-XBP1 signaling is emerging as a central orchestrator of malignant progression and immunosuppression in various cancer types. Employing a computational XBP1s detection method applied to TCGA datasets, we demonstrate that expression of the XBP1s mRNA isoform predicts poor survival in non-small cell lung cancer (NSCLC) patients. Ablation of IRE1α in malignant cells delays tumor progression and extends survival in mouse models of NSCLC. This protective effect is accompanied by alterations in intratumoral immune cell subsets eliciting durable adaptive anti-cancer immunity. Mechanistically, cancer cell-intrinsic IRE1α activation sustains mPGES-1 expression, enabling production of the immunosuppressive lipid mediator prostaglandin E2. Accordingly, restoring mPGES-1 expression in IRE1αKO cancer cells rescues normal tumor progression. We have developed an IRE1α gene signature that predicts immune cell infiltration and overall survival in human NSCLC. Our study unveils an immunoregulatory role for cancer cell-intrinsic IRE1α activation and suggests that targeting this pathway may help enhance anti-tumor immunity in NSCLC.
    DOI:  https://doi.org/10.1038/s41467-022-35584-9
  3. Sci Adv. 2023 Jan 06. 9(1): eade9120
    Arginine limitation drives a directed codon-dependent DNA sequence evolution response in colorectal cancer cells.
    Dennis J Hsu, Jenny Gao, Norihiro Yamaguchi, Alexandra Pinzaru, Qiushuang Wu, Nandan Mandayam, Maria Liberti, Søren Heissel, Hanan Alwaseem, Saeed Tavazoie, Sohail F Tavazoie.
      Utilization of specific codons varies between organisms. Cancer represents a model for understanding DNA sequence evolution and could reveal causal factors underlying codon evolution. We found that across human cancer, arginine codons are frequently mutated to other codons. Moreover, arginine limitation-a feature of tumor microenvironments-is sufficient to induce arginine codon-switching mutations in human colon cancer cells. Such DNA codon switching events encode mutant proteins with arginine residue substitutions. Mechanistically, arginine limitation caused rapid reduction of arginine transfer RNAs and the stalling of ribosomes over arginine codons. Such selective pressure against arginine codon translation induced an adaptive proteomic shift toward low-arginine codon-containing genes, including specific amino acid transporters, and caused mutational evolution away from arginine codons-reducing translational bottlenecks that occurred during arginine starvation. Thus, environmental availability of a specific amino acid can influence DNA sequence evolution away from its cognate codons and generate altered proteins.
    DOI:  https://doi.org/10.1126/sciadv.ade9120
  4. Cell. 2023 Jan 05. pii: S0092-8674(22)01520-3. [Epub ahead of print]186(1): 63-79.e21
    Cell-cell metabolite exchange creates a pro-survival metabolic environment that extends lifespan.
    Clara Correia-Melo, Stephan Kamrad, Roland Tengölics, Christoph B Messner, Pauline Trebulle, StJohn Townsend, Sreejith Jayasree Varma, Anja Freiwald, Benjamin M Heineike, Kate Campbell, Lucía Herrera-Dominguez, Simran Kaur Aulakh, Lukasz Szyrwiel, Jason S L Yu, Aleksej Zelezniak, Vadim Demichev, Michael Mülleder, Balázs Papp, Mohammad Tauqeer Alam, Markus Ralser.
      Metabolism is deeply intertwined with aging. Effects of metabolic interventions on aging have been explained with intracellular metabolism, growth control, and signaling. Studying chronological aging in yeast, we reveal a so far overlooked metabolic property that influences aging via the exchange of metabolites. We observed that metabolites exported by young cells are re-imported by chronologically aging cells, resulting in cross-generational metabolic interactions. Then, we used self-establishing metabolically cooperating communities (SeMeCo) as a tool to increase metabolite exchange and observed significant lifespan extensions. The longevity of the SeMeCo was attributable to metabolic reconfigurations in methionine consumer cells. These obtained a more glycolytic metabolism and increased the export of protective metabolites that in turn extended the lifespan of cells that supplied them with methionine. Our results establish metabolite exchange interactions as a determinant of cellular aging and show that metabolically cooperating cells can shape the metabolic environment to extend their lifespan.
    Keywords:  chronological aging; eukaryotic longevity; metabolic microenvironment; metabolite exchange interactions
    DOI:  https://doi.org/10.1016/j.cell.2022.12.007
  5. Blood. 2023 Jan 12. pii: blood.2022018258. [Epub ahead of print]
    Metabolism in stem cell driven leukaemia: parallels between haematopoiesis and immunity.
    Kevin M Rattigan, Martha M Zarou, Vignir Helgason.
      Our understanding of cancer metabolism spans from its role in cellular energetics and supplying the building blocks necessary for proliferation, to maintaining cellular redox and regulating the cellular epigenome and transcriptome. Cancer metabolism, once thought to be solely driven by upregulated glycolysis, is now known to comprise of multiple pathways with great plasticity in response to extrinsic challenges. Furthermore, cancer cells can modify their surrounding niche during disease initiation, maintenance and metastasis, contributing to therapy resistance. Leukaemia is a paradigm model of stem cell driven cancer. Here, we review how leukaemia remodels the niche and rewires its metabolism with particular attention paid to therapy-resistant stem cells. Specifically, we aim to give a global, non-exhaustive overview of key metabolic pathways. By contrasting the metabolic rewiring required by myeloid leukaemic stem cells with that required for haematopoiesis and immune cell function, we highlight the metabolic features they share. This is a critical consideration when contemplating anti-cancer metabolic inhibitor options, especially in the context of anti-cancer immune therapies. Finally, we examine pathways that have not been studied in leukaemia but are critical in solid cancers in the context of metastasis and interaction with new niches. These studies also offer detailed mechanisms that have yet to be investigated in leukaemia. Given that cancer (and normal) cells can meet their energy requirements by not only upregulating metabolic pathways, but also utilising systemically available substrates, we aim to inform how interlinked these metabolic pathways are, both within leukaemic cells and between cancer cells and their niche.
    DOI:  https://doi.org/10.1182/blood.2022018258
  6. Cell Rep. 2023 Jan 12. pii: S2211-1247(22)01891-5. [Epub ahead of print]42(1): 111987
    GOT1 regulates CD8+ effector and memory T cell generation.
    Wei Xu, Chirag H Patel, Liang Zhao, Im-Hong Sun, Min-Hee Oh, Im-Meng Sun, Rachel S Helms, Jiayu Wen, Jonathan D Powell.
      T cell activation, proliferation, function, and differentiation are tightly linked to proper metabolic reprogramming and regulation. By using [U-13C]glucose tracing, we reveal a critical role for GOT1 in promoting CD8+ T cell effector differentiation and function. Mechanistically, GOT1 enhances proliferation by maintaining intracellular redox balance and serine-mediated purine nucleotide biosynthesis. Further, GOT1 promotes the glycolytic programming and cytotoxic function of cytotoxic T lymphocytes via posttranslational regulation of HIF protein, potentially by regulating the levels of α-ketoglutarate. Conversely, genetic deletion of GOT1 promotes the generation of memory CD8+ T cells.
    Keywords:  CP: Metabolism; GOT1; HIF; NADH/NAD; effector and memory CD8(+) T cell; glucose; glutamate; serine
    DOI:  https://doi.org/10.1016/j.celrep.2022.111987
  7. Cancer Cell. 2023 Jan 03. pii: S1535-6108(22)00594-3. [Epub ahead of print]
    Intersection of immune and oncometabolic pathways drives cancer hyperprogression during immunotherapy.
    Gaopeng Li, Jae Eun Choi, Ilona Kryczek, Yilun Sun, Peng Liao, Shasha Li, Shuang Wei, Sara Grove, Linda Vatan, Reagan Nelson, Grace Schaefer, Steven G Allen, Kamya Sankar, Leslie A Fecher, Mishal Mendiratta-Lala, Timothy L Frankel, Angel Qin, Jessica J Waninger, Alangoya Tezel, Ajjai Alva, Christopher D Lao, Nithya Ramnath, Marcin Cieslik, Paul W Harms, Michael D Green, Arul M Chinnaiyan, Weiping Zou.
      Immune checkpoint blockade (ICB) can produce durable responses against cancer. We and others have found that a subset of patients experiences paradoxical rapid cancer progression during immunotherapy. It is poorly understood how tumors can accelerate their progression during ICB. In some preclinical models, ICB causes hyperprogressive disease (HPD). While immune exclusion drives resistance to ICB, counterintuitively, patients with HPD and complete response (CR) following ICB manifest comparable levels of tumor-infiltrating CD8+ T cells and interferon γ (IFNγ) gene signature. Interestingly, patients with HPD but not CR exhibit elevated tumoral fibroblast growth factor 2 (FGF2) and β-catenin signaling. In animal models, T cell-derived IFNγ promotes tumor FGF2 signaling, thereby suppressing PKM2 activity and decreasing NAD+, resulting in reduction of SIRT1-mediated β-catenin deacetylation and enhanced β-catenin acetylation, consequently reprograming tumor stemness. Targeting the IFNγ-PKM2-β-catenin axis prevents HPD in preclinical models. Thus, the crosstalk of core immunogenic, metabolic, and oncogenic pathways via the IFNγ-PKM2-β-catenin cascade underlies ICB-associated HPD.
    Keywords:  FGF2; IFNγ; PD-L1/PD-1 pathway; T cell immunity; complete response; glycolytic metabolism; hyperprogressive disease; immune checkpoint blockade; oncogenesis; β-catenin
    DOI:  https://doi.org/10.1016/j.ccell.2022.12.008
  8. Proc Natl Acad Sci U S A. 2023 Jan 17. 120(3): e2218332120
    OGT controls mammalian cell viability by regulating the proteasome/mTOR/ mitochondrial axis.
    Xiang Li, Xiaojing Yue, Hugo Sepulveda, Rajan A Burt, David A Scott, Steven A Carr, Samuel A Myers, Anjana Rao.
      O-GlcNAc transferase (OGT) modifies serine and threonine residues on nuclear and cytosolic proteins with O-linked N-acetylglucosamine (GlcNAc). OGT is essential for mammalian cell viability, but the underlying mechanisms are still enigmatic. We performed a genome-wide CRISPR-Cas9 screen in mouse embryonic stem cells (mESCs) to identify candidates whose depletion rescued the block in cell proliferation induced by OGT deficiency. We show that the block in cell proliferation in OGT-deficient cells stems from mitochondrial dysfunction secondary to mTOR (mechanistic target of rapamycin) hyperactivation. In normal cells, OGT maintains low mTOR activity and mitochondrial fitness through suppression of proteasome activity; in the absence of OGT, increased proteasome activity results in increased steady-state amino acid levels, which in turn promote mTOR lysosomal translocation and activation, and increased oxidative phosphorylation. mTOR activation in OGT-deficient mESCs was confirmed by an independent phospho-proteomic screen. Our study highlights a unique series of events whereby OGT regulates the proteasome/ mTOR/ mitochondrial axis in a manner that maintains homeostasis of intracellular amino acid levels, mitochondrial fitness, and cell viability. A similar mechanism operates in CD8+ T cells, indicating its generality across mammalian cell types. Manipulating OGT activity may have therapeutic potential in diseases in which this signaling pathway is impaired.
    Keywords:  OGT; genome-wide CRISPR/Cas9 screen; mTOR; mitochondrion; proteasome
    DOI:  https://doi.org/10.1073/pnas.2218332120
  9. Mol Cell. 2023 Jan 05. pii: S1097-2765(22)01170-4. [Epub ahead of print]83(1): 57-73.e9
    A central role for regulated protein stability in the control of TFE3 and MITF by nutrients.
    Christopher Nardone, Brad A Palanski, Daniel C Scott, Richard T Timms, Karl W Barber, Xin Gu, Aoyue Mao, Yumei Leng, Emma V Watson, Brenda A Schulman, Philip A Cole, Stephen J Elledge.
      The TFE3 and MITF master transcription factors maintain metabolic homeostasis by regulating lysosomal, melanocytic, and autophagy genes. Previous studies posited that their cytosolic retention by 14-3-3, mediated by the Rag GTPases-mTORC1, was key for suppressing transcriptional activity in the presence of nutrients. Here, we demonstrate using mammalian cells that regulated protein stability plays a fundamental role in their control. Amino acids promote the recruitment of TFE3 and MITF to the lysosomal surface via the Rag GTPases, activating an evolutionarily conserved phospho-degron and leading to ubiquitination by CUL1β-TrCP and degradation. Elucidation of the minimal functional degron revealed a conserved alpha-helix required for interaction with RagA, illuminating the molecular basis for a severe neurodevelopmental syndrome caused by missense mutations in TFE3 within the RagA-TFE3 interface. Additionally, the phospho-degron is recurrently lost in TFE3 genomic translocations that cause kidney cancer. Therefore, two divergent pathologies converge on the loss of protein stability regulation by nutrients.
    Keywords:  MITF; Rag GTPases; TFE3; kidney cancer; lysosomes; mTORC1; neurodevelopment; nutrient-sensing; phospho-degron; ubiquitin; β-TrCP
    DOI:  https://doi.org/10.1016/j.molcel.2022.12.013
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