bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2022–09–25
seven papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. Crosstalk between Hypoxia and Extracellular Matrix in the Tumor Microenvironment in Breast Cancer.
  2. Resveratrol reduces lactate production and modifies the ovarian cancer immune microenvironment.
  3. Ablation of the endoplasmic reticulum stress kinase PERK induces paraptosis and type I interferon to promote anti-tumor T cell responses.
  4. Stress-mediated attenuation of translation undermines T-cell activity in cancer.
  5. Exosome Release by Glucose Deprivation Is Important for the Viability of TSC-Null Cells.
  6. COX-2 upregulation by tumour cells post-chemotherapy fuels the immune evasive dark side of cancer inflammation.
  7. Stearoyl-CoA Desaturase Regulates Angiogenesis and Energy Metabolism in Ischemic Cardiomyocytes.
  1. Genes (Basel). 2022 Sep 03. pii: 1585. [Epub ahead of print]13(9):
    Crosstalk between Hypoxia and Extracellular Matrix in the Tumor Microenvironment in Breast Cancer.
    Yasmin Dekker, Sylvia E Le Dévédec, Erik H J Danen, Qiuyu Liu.
      Even though breast cancer is the most diagnosed cancer among women, treatments are not always successful in preventing its progression. Recent studies suggest that hypoxia and the extracellular matrix (ECM) are important in altering cell metabolism and tumor metastasis. Therefore, the aim of this review is to study the crosstalk between hypoxia and the ECM and to assess their impact on breast cancer progression. The findings indicate that hypoxic signaling engages multiple mechanisms that directly contribute to ECM remodeling, ultimately increasing breast cancer aggressiveness. Second, hypoxia and the ECM cooperate to alter different aspects of cell metabolism. They mutually enhance aerobic glycolysis through upregulation of glucose transport, glycolytic enzymes, and by regulating intracellular pH. Both alter lipid and amino acid metabolism by stimulating lipid and amino acid uptake and synthesis, thereby providing the tumor with additional energy for growth and metastasis. Third, YAP/TAZ signaling is not merely regulated by the tumor microenvironment and cell metabolism, but it also regulates it primarily through its target c-Myc. Taken together, this review provides a better understanding of the crosstalk between hypoxia and the ECM in breast cancer. Additionally, it points to a role for the YAP/TAZ mechanotransduction pathway as an important link between hypoxia and the ECM in the tumor microenvironment, driving breast cancer progression.
    Keywords:  YAP/TAZ; breast cancer; cell metabolism; extracellular matrix; hypoxia; mechanotransduction; tumor microenvironment
    DOI:  https://doi.org/10.3390/genes13091585
  2. Neoplasma. 2022 Sep 22. pii: 220414N410. [Epub ahead of print]
    Resveratrol reduces lactate production and modifies the ovarian cancer immune microenvironment.
    Jing Chen, Shu-Ting Huang, Jian-Guo Chen, Jian-Hui He, Wu-Mei Lin, Zhi-Hong Huang, Hai-Yan Ye, Shan-Yang He.
      Tumor cells show deregulated metabolism leading to an enrichment of lactate in the tumor microenvironment (TME). This lactate-rich environment has been reported to impair effector T cells. However, T-regulatory cells (Tregs) show metabolic advantages in lactate-rich TME that maintain a strong suppression of effector T cells, which leads to tumor immune evasion. Therefore, the glycolytic process of tumors could represent a therapeutic target, and agents that modify the energy metabolism of tumor cells have therapeutic potential. Resveratrol is a naturally occurring polyphenol that has been confirmed to suppress tumor cells' glycolytic metabolism. In this study, we show that resveratrol induces metabolic reprogramming in ovarian cancer cells. Resveratrol increases oxidative and decreases glycolysis, in association with decreased lactate production both in vitro and in vivo. Lactate reduction in TME weakens the suppressive function of Tregs, and subsequently restores anti-tumor immunity. Significantly, combined resveratrol and PD-1 blockade promote anti-tumor efficacy. These data suggest that resveratrol's anti-tumor actions in ovarian cancer could be explained, in part, through modification of the anti-tumor immunity, and indicate a novel treatment strategy for improving immune checkpoint blockade therapy using resveratrol.
    DOI:  https://doi.org/10.4149/neo_2022_220414N410
  3. Cancer Cell. 2022 Aug 29. pii: S1535-6108(22)00380-4. [Epub ahead of print]
    Ablation of the endoplasmic reticulum stress kinase PERK induces paraptosis and type I interferon to promote anti-tumor T cell responses.
    Jessica K Mandula, Shiun Chang, Eslam Mohamed, Rachel Jimenez, Rosa A Sierra-Mondragon, Darwin C Chang, Alyssa N Obermayer, Carlos M Moran-Segura, Satyajit Das, Julio A Vazquez-Martinez, Karol Prieto, Ann Chen, Keiran S M Smalley, Brian Czerniecki, Peter Forsyth, Richard C Koya, Brian Ruffell, Juan R Cubillos-Ruiz, David H Munn, Timothy I Shaw, Jose R Conejo-Garcia, Paulo C Rodriguez.
      Activation of unfolded protein responses (UPRs) in cancer cells undergoing endoplasmic reticulum (ER) stress promotes survival. However, how UPR in tumor cells impacts anti-tumor immune responses remains poorly described. Here, we investigate the role of the UPR mediator pancreatic ER kinase (PKR)-like ER kinase (PERK) in cancer cells in the modulation of anti-tumor immunity. Deletion of PERK in cancer cells or pharmacological inhibition of PERK in melanoma-bearing mice incites robust activation of anti-tumor T cell immunity and attenuates tumor growth. PERK elimination in ER-stressed malignant cells triggers SEC61β-induced paraptosis, thereby promoting immunogenic cell death (ICD) and systemic anti-tumor responses. ICD induction in PERK-ablated tumors stimulates type I interferon production in dendritic cells (DCs), which primes CCR2-dependent tumor trafficking of common-monocytic precursors and their intra-tumor commitment into monocytic-lineage inflammatory Ly6C+CD103+ DCs. These findings identify how tumor cell-derived PERK promotes immune evasion and highlight the potential of PERK-targeting therapies in cancer immunotherapy.
    Keywords:  PERK; immunogenic cell death; tumor immunity; type I IFN; unfolded protein responses
    DOI:  https://doi.org/10.1016/j.ccell.2022.08.016
  4. Cancer Res. 2022 Sep 20. pii: CAN-22-1744. [Epub ahead of print]
    Stress-mediated attenuation of translation undermines T-cell activity in cancer.
    Brian P Riesenberg, Elizabeth G Hunt, Megan D Tennant, Katie E Hurst, Alex M Andrews, Lee R Leddy, David M Neskey, Elizabeth G Hill, Guillermo O Rangel Rivera, Chrystal M Paulos, Peng Gao, Jessica E Thaxton.
      Protein synthesis supports robust immune responses. Nutrient competition and global cell stressors in the tumor microenvironment (TME) may impact protein translation in T cells and antitumor immunity. Using human and mouse tumors, we demonstrated here that protein translation in T cells is repressed in solid tumors. Reduced glucose availability to T cells in the TME led to activation of the unfolded protein response (UPR) element eIF2a. Genetic mouse models revealed that translation attenuation mediated by activated p-eIF2a undermines the ability of T cells to suppress tumor growth. Reprogramming T cell metabolism was able to alleviate p-eIF2a accumulation and translational attenuation in the TME, allowing for sustained protein translation. Metabolic and pharmacological approaches showed that proteasome activity mitigates induction of p-eIF2a to support optimal antitumor T cell function, protecting from translation attenuation and enabling prolonged cytokine synthesis in solid tumors. Together, these data identify a new therapeutic avenue to fuel the efficacy of tumor immunotherapy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-1744
  5. Cells. 2022 Sep 14. pii: 2862. [Epub ahead of print]11(18):
    Exosome Release by Glucose Deprivation Is Important for the Viability of TSC-Null Cells.
    Ji-Hyun Bae, Jong Hyun Kim.
      The control of exosome release is associated with numerous physiological and pathological activities, and that release is often indicative of health, disease, and environmental nutrient stress. Tuberous sclerosis complex (TSC) regulates the cell viability via the negative regulation of the mammalian target of rapamycin complex (mTORC1) during glucose deprivation. However, the mechanism by which viability of TSC-null cells is regulated by mTORC1 inhibition under glucose deprivation remains unclear. Here, we demonstrated that exosome release regulates cell death induced by glucose deprivation in TSC-null cells. The mTORC1 inhibition by rapamycin significantly increased the exosome biogenesis, exosome secretion, and cell viability in TSC-null cells. In addition, the increase in cell viability by mTORC1 inhibition was attenuated by two different types of inhibitors of exosome release under glucose deprivation. Taken together, we suggest that exosome release inhibition might be a novel way for regression of cell growth in TSC-null cells showing lack of cell death by mTORC1 inhibition.
    Keywords:  TSC; cell viability; exosome; glucose deprivation; mTORC1
    DOI:  https://doi.org/10.3390/cells11182862
  6. Cell Stress. 2022 Sep;6(9): 76-78
    COX-2 upregulation by tumour cells post-chemotherapy fuels the immune evasive dark side of cancer inflammation.
    Charlotte R Bell, Santiago Zelenay.
      Cytotoxic therapies, such as chemotherapy and radiotherapy, are mainstays of cancer treatment for both early and unresectable, advanced disease. In addition to debulking the tumour mass through direct killing of proliferating tumour cells, these treatments can promote tumour control via immune-stimulating effects. Nonetheless, chemoresistance and tumour relapse remain huge clinical problems, suggesting that induction of anti-cancer immunity post-cytotoxic therapy is often weak, not durable and/or overcome by immune evasive mechanisms. In our recent study (Nat Commun 13:2063), we demonstrate that cancer cell-intrinsic activation of the cyclooxygenase (COX)-2/prostaglandin E2 (PGE2) pathway post-chemotherapy treatment is a prevalent phenomenon which profoundly alters the inflammatory properties of the treated cancer cells. Of particular translational relevance, our findings support a model whereby upregulation of COX-2 expression and activity post-chemotherapy impairs the efficacy of the combination of PD-1 blockade and chemotherapy. Accordingly, pharmacological inhibition of COX-2 with celecoxib, an anti-inflammatory drug already used clinically, unleashed tumour control in preclinical models when given alongside chemoimmunotherapy combinations.
    Keywords:  COX-2; cancer inflammation; chemotherapy; immune checkpoint blockade therapy; prostaglandin E2
    DOI:  https://doi.org/10.15698/cst2022.09.271
  7. Int J Mol Sci. 2022 Sep 09. pii: 10459. [Epub ahead of print]23(18):
    Stearoyl-CoA Desaturase Regulates Angiogenesis and Energy Metabolism in Ischemic Cardiomyocytes.
    Ana-Maria Gan, Zuzanna Tracz-Gaszewska, Aleksandra Ellert-Miklaszewska, Viktor O Navrulin, James M Ntambi, Pawel Dobrzyn.
      New blood vessel formation is a key component of the cardiac repair process after myocardial infarction (MI). Hypoxia following MI is a major driver of angiogenesis in the myocardium. Hypoxia-inducible factor 1α (HIF1α) is the key regulator of proangiogenic signaling. The present study found that stearoyl-CoA desaturase (SCD) significantly contributed to the induction of angiogenesis in the hypoxic myocardium independently of HIF1α expression. The pharmacological inhibition of SCD activity in HL-1 cardiomyocytes and SCD knockout in an animal model disturbed the expression and secretion of proangiogenic factors including vascular endothelial growth factor-A, proinflammatory cytokines (interleukin-1β, interleukin-6, tumor necrosis factor α, monocyte chemoattractant protein-1, and Rantes), metalloproteinase-9, and platelet-derived growth factor in ischemic cardiomyocytes. These disturbances affected the proangiogenic potential of ischemic cardiomyocytes after SCD depletion. Together with the most abundant SCD1 isoform, the heart-specific SCD4 isoform emerged as an important regulator of new blood vessel formation in the murine post-MI myocardium. We also provide evidence that SCD shapes energy metabolism of the ischemic heart by maintaining the shift from fatty acids to glucose as the substrate that is used for adenosine triphosphate production. Furthermore, we propose that the regulation of the proangiogenic properties of hypoxic cardiomyocytes by key modulators of metabolic signaling such as adenosine monophosphate kinase, protein kinase B (AKT), and peroxisome-proliferator-activated receptor-γ coactivator 1α/peroxisome proliferator-activated receptor α depends on SCD to some extent. Thus, our results reveal a novel mechanism that links SCD to cardiac repair processes after MI.
    Keywords:  cytokines; fatty acids; heart; hypoxia; substrate utilization
    DOI:  https://doi.org/10.3390/ijms231810459
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