bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2024–10–06
eight papers selected by
Oltea Sampetrean, Keio University
  1. Identifying metabolic limitations in the tumor microenvironment.
  2. The metabolic crosstalk of cancer-associated fibroblasts and tumor cells: Recent advances and future perspectives.
  3. Focusing on CD8+ T-cell phenotypes: improving solid tumor therapy.
  4. Hexosaminidase B-driven cancer cell-macrophage co-dependency promotes glycolysis addiction and tumorigenesis in glioblastoma.
  5. Macrophages and T cells in metabolic disorder-associated cancers.
  6. Fatty acid synthase (FASN) is a tumor-cell-intrinsic metabolic checkpoint restricting T-cell immunity.
  7. Cholesterol metabolism: a positive target to revoke the function of exhausted CAR-NK cells in tumor microenvironment.
  8. Hypoxia induces ROS-resistant memory upon reoxygenation in vivo promoting metastasis in part via MUC1-C.
  1. Sci Adv. 2024 Oct 04. 10(40): eadq7305
    Identifying metabolic limitations in the tumor microenvironment.
    Guillaume Cognet, Alexander Muir.
      Solid tumors are characterized by dysfunctional vasculature that limits perfusion and delivery of nutrients to the tumor microenvironment. Limited perfusion coupled with the high metabolic demand of growing tumors has led to the hypothesis that many tumors experience metabolic stress driven by limited availability of nutrients such as glucose, oxygen, and amino acids in the tumor. Such metabolic stress has important implications for the biology of cells in the microenvironment, affecting both disease progression and response to therapies. Recently, techniques have been developed to identify limiting nutrients and resulting metabolic stresses in solid tumors. These techniques have greatly expanded our understanding of the metabolic limitations in tumors. This review will discuss these experimental tools and the emerging picture of metabolic limitations in tumors arising from recent studies using these approaches.
    DOI:  https://doi.org/10.1126/sciadv.adq7305
  2. Biochim Biophys Acta Rev Cancer. 2024 Sep 26. pii: S0304-419X(24)00121-5. [Epub ahead of print]1879(6): 189190
    The metabolic crosstalk of cancer-associated fibroblasts and tumor cells: Recent advances and future perspectives.
    Bing Xia, Liqing Qiu, Jing Yue, Jingxing Si, Hongfang Zhang.
      Tumor cells grow in a microenvironment with a lack of nutrients and oxygen. Cancer-associated fibroblasts (CAFs) as one major component of tumor microenvironment have strong ability to survive under stressful conditions through metabolic remodelling. Furthermore, CAFs are educated by tumor cells and help them adapt to the hostile microenvironment through their metabolic communication. By inducing catabolism, CAFs release nutrients into the microenvironment which are taken up by tumor cells to satisfy their metabolic requirements. Furthermore, CAFs can recycle toxic metabolic wastes produced by cancer cells into energetic substances, allowing cancer cells to undergo biosynthesis. Their metabolic crosstalk also enhances CAFs' pro-tumor phenotype and reshape the microenvironment facilitating tumor cells' metastasis and immune escape. In this review, we have analyzed the effect and mechanisms of metabolic crosstalk between tumor cells and CAFs. We also analyzed the future perspectives in this area from the points of CAFs heterogeneity, spatial metabonomics and patient-derived tumor organoids (PDOs). These information may deepen the knowledge of tumor metabolism regulated by CAFs and provide novel insights into the development of metabolism-based anti-cancer strategies.
    Keywords:  Anti-cancer strategies; CAFs; Environmental stress; Metabolic crosstalk; Tumor-promoting roles
    DOI:  https://doi.org/10.1016/j.bbcan.2024.189190
  3. J Exp Clin Cancer Res. 2024 Sep 28. 43(1): 266
    Focusing on CD8+ T-cell phenotypes: improving solid tumor therapy.
    Zhouchi Yao, Yayun Zeng, Cheng Liu, Huimin Jin, Hong Wang, Yue Zhang, Chengming Ding, Guodong Chen, Daichao Wu.
      Vigorous CD8+ T cells play a crucial role in recognizing tumor cells and combating solid tumors. How T cells efficiently recognize and target tumor antigens, and how they maintain the activity in the "rejection" of solid tumor microenvironment, are major concerns. Recent advances in understanding of the immunological trajectory and lifespan of CD8+ T cells have provided guidance for the design of more optimal anti-tumor immunotherapy regimens. Here, we review the newly discovered methods to enhance the function of CD8+ T cells against solid tumors, focusing on optimizing T cell receptor (TCR) expression, improving antigen recognition by engineered T cells, enhancing signal transduction of the TCR-CD3 complex, inducing the homing of polyclonal functional T cells to tumors, reversing T cell exhaustion under chronic antigen stimulation, and reprogramming the energy and metabolic pathways of T cells. We also discuss how to participate in the epigenetic changes of CD8+ T cells to regulate two key indicators of anti-tumor responses, namely effectiveness and persistence.
    Keywords:  CD8+ T cell; Engineered T cell receptor -T cells; Gene editing; Immune checkpoint; Immune reprogramming; Immunotherapy; Metabolic reprogramming; Solid tumor; T cell redirection
    DOI:  https://doi.org/10.1186/s13046-024-03195-5
  4. Nat Commun. 2024 Oct 01. 15(1): 8506
    Hexosaminidase B-driven cancer cell-macrophage co-dependency promotes glycolysis addiction and tumorigenesis in glioblastoma.
    Chen Zhu, Xin Chen, Tian-Qi Liu, Lin Cheng, Wen Cheng, Peng Cheng, An-Hua Wu.
      Glycolytic metabolic reprogramming in cancer is regulated by both cancer intrinsic variations like isocitrate dehydrogenase 1 (IDH1) status and non-cancerous microenvironment components like tumor associated macrophages (TAMs). However, the detailed mechanism remains elusive. Here, we identify hexosaminidase B (HEXB) as a key regulator for glycolysis in glioblastoma (GBM). HEXB intercellularly manipulates TAMs to promote glycolysis in GBM cells, while intrinsically enhancing cancer cell glycolysis. Mechanistically, HEXB elevation augments tumor HIF1α protein stability through activating ITGB1/ILK/YAP1; Subsequently, HIF1α promotes HEXB and multiple glycolytic gene transcription in GBM cells. Genetic ablation and pharmacological inhibition of HEXB elicits substantial therapeutic effects in preclinical GBM models, while targeting HEXB doesn't induce significant reduction in IDH1 mutant glioma and inhibiting IDH1 mutation-derived 2-hydroxyglutaric acid (2-HG) significantly restores HEXB expression in glioma cells. Our work highlights a HEXB driven TAMs-associated glycolysis-promoting network in GBM and provides clues for developing more effective therapies against it.
    DOI:  https://doi.org/10.1038/s41467-024-52888-0
  5. Nat Rev Cancer. 2024 Oct 01.
    Macrophages and T cells in metabolic disorder-associated cancers.
    Daniel Taranto, Daan J Kloosterman, Leila Akkari.
      Cancer and metabolic disorders have emerged as major global health challenges, reaching epidemic levels in recent decades. Often viewed as separate issues, metabolic disorders are shown by mounting evidence to heighten cancer risk and incidence. The intricacies underlying this connection are still being unraveled and encompass a complex interplay between metabolites, cancer cells and immune cells within the tumour microenvironment (TME). Here, we outline the interplay between metabolic and immune cell dysfunction in the context of three highly prevalent metabolic disorders, namely obesity; two associated liver diseases, metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH); and type 2 diabetes. We focus primarily on macrophages and T cells, the critical roles of which in dictating inflammatory response and immune surveillance in metabolic disorder-associated cancers are widely reported. Moreover, considering the ever-increasing number of patients prescribed with metabolism disorder-altering drugs and diets in recent years, we discuss how these therapies modulate systemic and local immune phenotypes, consequently impacting cancer malignancy. Collectively, unraveling the determinants of metabolic disorder-associated immune landscape and their role in fuelling cancer malignancy will provide a framework essential to therapeutically address these highly prevalent diseases.
    DOI:  https://doi.org/10.1038/s41568-024-00743-1
  6. Cell Death Discov. 2024 Sep 30. 10(1): 417
    Fatty acid synthase (FASN) is a tumor-cell-intrinsic metabolic checkpoint restricting T-cell immunity.
    Elisabet Cuyàs, Stefano Pedarra, Sara Verdura, Miguel Angel Pardo, Roderic Espin Garcia, Eila Serrano-Hervás, Àngela Llop-Hernández, Eduard Teixidor, Joaquim Bosch-Barrera, Eugeni López-Bonet, Begoña Martin-Castillo, Ruth Lupu, Miguel Angel Pujana, Josep Sardanyès, Tomás Alarcón, Javier A Menendez.
      Fatty acid synthase (FASN)-catalyzed endogenous lipogenesis is a hallmark of cancer metabolism. However, whether FASN is an intrinsic mechanism of tumor cell defense against T cell immunity remains unexplored. To test this hypothesis, here we combined bioinformatic analysis of the FASN-related immune cell landscape, real-time assessment of cell-based immunotherapy efficacy in CRISPR/Cas9-based FASN gene knockout (FASN KO) cell models, and mathematical and mechanistic evaluation of FASN-driven immunoresistance. FASN expression negatively correlates with infiltrating immune cells associated with cancer suppression, cytolytic activity signatures, and HLA-I expression. Cancer cells engineered to carry a loss-of-function mutation in FASN exhibit an enhanced cytolytic response and an accelerated extinction kinetics upon interaction with cytokine-activated T cells. Depletion of FASN results in reduced carrying capacity, accompanied by the suppression of mitochondrial OXPHOS and strong downregulation of electron transport chain complexes. Targeted FASN depletion primes cancer cells for mitochondrial apoptosis as it synergizes with BCL-2/BCL-XL-targeting BH3 mimetics to render cancer cells more susceptible to T-cell-mediated killing. FASN depletion prevents adaptive induction of PD-L1 in response to interferon-gamma and reduces constitutive overexpression of PD-L1 by abolishing PD-L1 post-translational palmitoylation. FASN is a novel tumor cell-intrinsic metabolic checkpoint that restricts T cell immunity and may be exploited to improve the efficacy of T cell-based immunotherapy.
    DOI:  https://doi.org/10.1038/s41420-024-02184-z
  7. Front Pharmacol. 2024 ;15 1440869
    Cholesterol metabolism: a positive target to revoke the function of exhausted CAR-NK cells in tumor microenvironment.
    Jingfeng Liu.
      
    Keywords:  CAR (chimeric antigen receptor); NK cell; cholesterol; metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3389/fphar.2024.1440869
  8. Nat Commun. 2024 Sep 28. 15(1): 8416
    Hypoxia induces ROS-resistant memory upon reoxygenation in vivo promoting metastasis in part via MUC1-C.
    Inês Godet, Harsh H Oza, Yi Shi, Natalie S Joe, Alyssa G Weinstein, Jeanette Johnson, Michael Considine, Swathi Talluri, Jingyuan Zhang, Reid Xu, Steven Doctorman, Delma Mbulaiteye, Genevieve Stein-O'Brien, Luciane T Kagohara, Cesar A Santa-Maria, Elana J Fertig, Daniele M Gilkes.
      Hypoxia occurs in 90% of solid tumors and is associated with metastasis and mortality. Breast cancer cells that experience intratumoral hypoxia are 5x more likely to develop lung metastasis in animal models. Using spatial transcriptomics, we determine that hypoxic cells localized in more oxygenated tumor regions (termed 'post-hypoxic') retain expression of hypoxia-inducible and NF-kB-regulated genes, even in the oxygen-rich bloodstream. This cellular response is reproduced in vitro under chronic hypoxic conditions followed by reoxygenation. A subset of genes remains increased in reoxygenated cells. MUC1/MUC1-C is upregulated by both HIF-1α and NF-kB-p65 during chronic hypoxia. Abrogating MUC1 decreases the expression of superoxide dismutase enzymes, causing reactive oxygen species (ROS) production and cell death. A hypoxia-dependent genetic deletion of MUC1, or MUC1-C inhibition by GO-203, increases ROS levels in circulating tumor cells (CTCs), reducing the extent of metastasis. High MUC1 expression in tumor biopsies is associated with recurrence, and MUC1+ CTCs have lower ROS levels than MUC1- CTCs in patient-derived xenograft models. This study demonstrates that therapeutically targeting MUC1-C reduces hypoxia-driven metastasis.
    DOI:  https://doi.org/10.1038/s41467-024-51995-2
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