bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2023–07–16
six papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. Physiological role of cytokines in the regulation of mammalian metabolism.
  2. The stress sensor GCN2 differentially controls ribosome biogenesis in colon cancer according to the nutritional context.
  3. Targeting tumor O-glycosylation modulates cancer-immune-cell crosstalk and enhances anti-PD-1 immunotherapy in head and neck cancer.
  4. Inhibition of protein translation under matrix-deprivation stress in breast cancer cells.
  5. Tumor-associated macrophages: new insights on their metabolic regulation and their influence in cancer immunotherapy.
  6. Hypoxic niches attract and sequester tumor-associated macrophages and cytotoxic T cells and reprogram them for immunosuppression.
  1. Trends Immunol. 2023 Jul 07. pii: S1471-4906(23)00110-2. [Epub ahead of print]
    Physiological role of cytokines in the regulation of mammalian metabolism.
    Axel de Baat, Beckey Trinh, Helga Ellingsgaard, Marc Y Donath.
      The innate cytokine system is involved in the response to excessive food intake. In this review, we highlight recent advances in our understanding of the physiological role of three prominent cytokines, interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF), in mammalian metabolic regulation. This recent research highlights the pleiotropic and context-dependent functions in the immune-metabolic interplay. IL-1β is activated in response to overloaded mitochondrial metabolism, stimulates insulin secretion, and allocates energy to immune cells. IL-6 is released by contracting skeletal muscle and adipose tissue and directs energy from storing tissues to consuming tissues. TNF induces insulin resistance and prevents ketogenesis. Additionally, the therapeutic potential of modulating the activity of each cytokine is discussed.
    Keywords:  cytokine; diabetes; humans; insulin; metabolism; obesity
    DOI:  https://doi.org/10.1016/j.it.2023.06.002
  2. Mol Oncol. 2023 Jul 15.
    The stress sensor GCN2 differentially controls ribosome biogenesis in colon cancer according to the nutritional context.
    Marie Piecyk, Mouna Triki, Pierre-Alexandre Laval, Cedric Duret, Joelle Fauvre, Laura Cussonneau, Christelle Machon, Jerôme Guitton, Nicolas Rama, Benjamin Gibert, Gabriel Ichim, Frederic Catez, Fleur Bourdelais, Sebastien Durand, Jean-Jacques Diaz, Isabelle Coste, Toufic Renno, Serge N Manié, Nicolas Aznar, Stephane Ansieau, Carole Ferraro-Peyret, Cedric Chaveroux.
      Nutrient availability is a key determinant of tumor cell behavior. While nutrient-rich conditions favor proliferation and tumor growth, scarcity, and particularly glutamine starvation, promotes cell dedifferentiation and chemoresistance. Here, linking ribosome biogenesis plasticity with tumor cell fate, we uncover that the amino acid sensor general control non-derepressible 2 (GCN2; also known as eIF-2-alpha kinase 4) represses the expression of the precursor of ribosomal RNA (rRNA), 47S, under metabolic stress. We show that blockade of GCN2 triggers cell death by an irremediable nucleolar stress and subsequent TP53-mediated apoptosis in patient-derived models of colon adenocarcinoma (COAD). In nutrient-rich conditions, a cell-autonomous GCN2 activity supports cell proliferation by stimulating 47S rRNA transcription, independently of the canonical integrated stress response (ISR) axis. Impairment of GCN2 activity prevents nuclear translocation of methionyl-tRNA synthetase (MetRS), resulting in nucleolar stress, mTORC1 inhibition and, ultimately, autophagy induction. Inhibition of the GCN2-MetRS axis drastically improves the cytotoxicity of RNA polymerase I (RNA pol I) inhibitors, including the first-line chemotherapy oxaliplatin, on patient-derived COAD tumoroids. Our data thus reveal that GCN2 differentially controls ribosome biogenesis according to the nutritional context. Furthermore, pharmacological co-inhibition of the two GCN2 branches and RNA pol I activity may represent a valuable strategy for elimination of proliferative and metabolically-stressed COAD cells.
    Keywords:  Colon cancer; GCN2; Methionyl-tRNA synthetase; Nucleolar stress; Ribosome biogenesis
    DOI:  https://doi.org/10.1002/1878-0261.13491
  3. Mol Oncol. 2023 Jul 15.
    Targeting tumor O-glycosylation modulates cancer-immune-cell crosstalk and enhances anti-PD-1 immunotherapy in head and neck cancer.
    Mei-Chun Lin, Ya-Ting Chuang, Hsin-Yi Wu, Chia-Lang Hsu, Neng-Yu Lin, Min-Chuan Huang, Pei-Jen Lou.
      Cells in the tumor microenvironment (TME) communicate via membrane-bound and secreted proteins, which are mostly glycosylated. Altered glycomes of malignant tumors influence behaviors of stromal cells. In this study, we showed that the loss of core-1 β1,3-galactosyltransferase (C1GALT1)-mediated O-glycosylation suppressed tumor growth in syngeneic head and neck cancer (HNC) mouse models. O-glycan truncation in tumor cells promoted the M1 polarization of macrophages, enhanced T-cell-mediated cytotoxicity, and reduced interleukin-6 (IL-6) levels in the secretome. Proteasomal degradation of IL-6 was controlled by the O-glycan at threonine 166. Both IL-6/IL-6R blockade and O-glycan truncation in tumor cells induced similar pro-inflammatory phenotypes in macrophages and cytotoxic T lymphocytes (CTLs). The combination of the O-glycosylation inhibitor itraconazole and anti-programmed cell death protein 1 (anti-PD-1) antibody effectively suppressed tumor growth in vivo. Collectively, our findings demonstrate that O-glycosylation in tumor cells governs their crosstalk with macrophages and CTLs. Thus, targeting O-glycosylation successfully reshapes the TME and consequently enhances the efficacy of anti-PD-1 therapy.
    Keywords:  IL-6; Itraconazole; O-glycosylation; PD-1; Tumor microenvironment (TME); core 1 β1,3-galactosyltransferase (C1GALT1); head and neck cancer (HNC); immune checkpoint inhibitor (ICI)
    DOI:  https://doi.org/10.1002/1878-0261.13489
  4. Front Med (Lausanne). 2023 ;10 1124514
    Inhibition of protein translation under matrix-deprivation stress in breast cancer cells.
    Shweta Warrier, Shivaani Srinivasan, Adithya Chedere, Annapoorni Rangarajan.
      Matrix-deprivation stress leads to cell-death by anoikis, whereas overcoming anoikis is critical for cancer metastasis. Work from our lab and others has identified a crucial role for the cellular energy sensor AMPK in anoikis-resistance, highlighting a key role for metabolic reprogramming in stress survival. Protein synthesis is a major energy-consuming process that is tightly regulated under stress. Although an increase in protein synthesis in AMPK-depleted experimentally-transformed MEFs has been associated with anoikis, the status and regulation of protein translation in epithelial-origin cancer cells facing matrix-detachment remains largely unknown. Our study shows that protein translation is mechanistically abrogated at both initiation and elongation stages by the activation of the unfolded protein response (UPR) pathway and inactivation of elongation factor eEF2, respectively. Additionally, we show inhibition of the mTORC1 pathway known for regulation of canonical protein synthesis. We further functionally assay this inhibition using SUnSET assay, which demonstrates repression of global protein synthesis in MDA-MB-231 and MCF7 breast cancer cells when subjected to matrix-deprivation. In order to gauge the translational status of matrix-deprived cancer cells, we undertook polysome profiling. Our data revealed reduced but continuous mRNA translation under matrix-deprivation stress. An integrated analysis of transcriptomic and proteomic data further identifies novel targets that may aid cellular adaptations to matrix-deprivation stress and can be explored for therapeutic intervention.
    Keywords:  ISR; SUnSET; mTORC1; matrix-deprivation; polysome; protein translation; stress; translatome
    DOI:  https://doi.org/10.3389/fmed.2023.1124514
  5. Front Immunol. 2023 ;14 1157291
    Tumor-associated macrophages: new insights on their metabolic regulation and their influence in cancer immunotherapy.
    Li Xiao, Qiao Wang, Hongling Peng.
      Tumor-associated macrophages (TAMs) are a dynamic and heterogeneous cell population of the tumor microenvironment (TME) that plays an essential role in tumor formation and progression. Cancer cells have a high metabolic demand for their rapid proliferation, survival, and progression. A comprehensive interpretation of pro-tumoral and antitumoral metabolic changes in TAMs is crucial for comprehending immune evasion mechanisms in cancer. The metabolic reprogramming of TAMs is a novel method for enhancing their antitumor effects. In this review, we provide an overview of the recent research on metabolic alterations of TAMs caused by TME, focusing primarily on glucose, amino acid, and fatty acid metabolism. In addition, this review discusses antitumor immunotherapies that influence the activity of TAMs by limiting their recruitment, triggering their depletion, and re-educate them, as well as metabolic profiles leading to an antitumoral phenotype. We highlighted the metabolic modulational roles of TAMs and their potential to enhance immunotherapy for cancer.
    Keywords:  amino acid metabolism; fatty acid metabolism; glucose metabolism; immunotherapy; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.3389/fimmu.2023.1157291
  6. Immunity. 2023 Jul 07. pii: S1074-7613(23)00274-1. [Epub ahead of print]
    Hypoxic niches attract and sequester tumor-associated macrophages and cytotoxic T cells and reprogram them for immunosuppression.
    Anirudh Sattiraju, Sangjo Kang, Bruno Giotti, Zhihong Chen, Valerie J Marallano, Concetta Brusco, Aarthi Ramakrishnan, Li Shen, Alexander M Tsankov, Dolores Hambardzumyan, Roland H Friedel, Hongyan Zou.
      Glioblastoma (GBM), a highly lethal brain cancer, is notorious for immunosuppression, but the mechanisms remain unclear. Here, we documented a temporospatial patterning of tumor-associated myeloid cells (TAMs) corresponding to vascular changes during GBM progression. As tumor vessels transitioned from the initial dense regular network to later scant and engorged vasculature, TAMs shifted away from perivascular regions and trafficked to vascular-poor areas. This process was heavily influenced by the immunocompetence state of the host. Utilizing a sensitive fluorescent UnaG reporter to track tumor hypoxia, coupled with single-cell transcriptomics, we revealed that hypoxic niches attracted and sequestered TAMs and cytotoxic T lymphocytes (CTLs), where they were reprogrammed toward an immunosuppressive state. Mechanistically, we identified chemokine CCL8 and cytokine IL-1β as two hypoxic-niche factors critical for TAM trafficking and co-evolution of hypoxic zones into pseudopalisading patterns. Therefore, perturbation of TAM patterning in hypoxic zones may improve tumor control.
    Keywords:  CCL8; CTLs; GBM; IL-1β; TAM; cytotoxic T lymphocytes; immune landscape; immunosuppression; tumor hypoxia; tumor vasculature; tumor-associated microglia/macrophages
    DOI:  https://doi.org/10.1016/j.immuni.2023.06.017
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