bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2022–10–30
seven papers selected by
Linda Chan, Yale University
  1. Reprogramming Carbohydrate Metabolism in Cancer and Its Role in Regulating the Tumor Microenvironment.
  2. Metabolic features of innate lymphoid cells.
  3. Link between glucose metabolism and epithelial-to-mesenchymal transition drives triple-negative breast cancer migratory heterogeneity.
  4. Lactate dehydrogenases promote glioblastoma growth and invasion via a metabolic symbiosis.
  5. Metabolic control of CD47 expression through LAT2-mediated amino acid uptake promotes tumor immune evasion.
  6. Limiting glutamine utilization activates a GCN2/TRAIL-R2/Caspase-8 apoptotic pathway in glutamine-addicted tumor cells.
  7. Autophagy in Cancer: A Metabolic Perspective.
  1. Subcell Biochem. 2022 ;100 3-65
    Reprogramming Carbohydrate Metabolism in Cancer and Its Role in Regulating the Tumor Microenvironment.
    Swagata Adhikari, Deblina Guha, Chitra Mohan, Shravanti Mukherjee, Jessica K Tyler, Chandrima Das.
      Altered metabolism has become an emerging feature of cancer cells impacting their proliferation and metastatic potential in myriad ways. Proliferating heterogeneous tumor cells are surrounded by other resident or infiltrating cells, along with extracellular matrix proteins, and other secretory factors constituting the tumor microenvironment. The diverse cell types of the tumor microenvironment exhibit different molecular signatures that are regulated at their genetic and epigenetic levels. The cancer cells elicit intricate crosstalks with these supporting cells, exchanging essential metabolites which support their anabolic processes and can promote their survival, proliferation, EMT, angiogenesis, metastasis and even therapeutic resistance. In this context, carbohydrate metabolism ensures constant energy supply being a central axis from which other metabolic and biosynthetic pathways including amino acid and lipid metabolism and pentose phosphate pathway are diverged. In contrast to normal cells, increased glycolytic flux is a distinguishing feature of the highly proliferative cancer cells, which supports them to adapt to a hypoxic environment and also protects them from oxidative stress. Such rewired metabolic properties are often a result of epigenetic alterations in the cancer cells, which are mediated by several factors including, DNA, histone and non-histone protein modifications and non-coding RNAs. Conversely, epigenetic landscapes of the cancer cells are also dictated by their diverse metabolomes. Altogether, this metabolic and epigenetic interplay has immense potential for the development of efficient anti-cancer therapeutic strategies. In this book chapter we emphasize upon the significance of reprogrammed carbohydrate metabolism in regulating the tumor microenvironment and cancer progression, with an aim to explore the different metabolic and epigenetic targets for better cancer treatment.
    Keywords:  Acetyl-CoA; Carbohydrate metabolism; DNMTs; Epigenetics; Glycolytic flux; HATs; HDACs; HDM; HMT; Hypoxia; Metabolic reprogramming; Metastasis; OXPHOS; Oncometabolites; SAM; Tumor microenvironment
    DOI:  https://doi.org/10.1007/978-3-031-07634-3_1
  2. J Exp Med. 2022 Nov 07. pii: e20221140. [Epub ahead of print]219(11):
    Metabolic features of innate lymphoid cells.
    Huiyang Yu, Nicolas Jacquelot, Gabrielle T Belz.
      Innate and adaptive immune cells are found in distinct tissue niches where they orchestrate immune responses. This requires intrinsic and temporal metabolic adaptability to coordinately activate the immune response cascade. Dysregulation of this program is a key feature of immunosuppression. Direct or indirect metabolic immune cell reprogramming may offer new approaches to modulate immune cells behavior for therapy to overcome dysregulation. In this review, we explored how metabolism regulates lymphocytes beyond the classical T cell subsets. We focus on the innate lymphoid cell (ILC) family, highlighting the distinct metabolic characteristics of these cells, the impact of environmental factors, and the receptors that could alter immune cell functions through manipulation of metabolic pathways to potentially prevent or treat various diseases.
    DOI:  https://doi.org/10.1084/jem.20221140
  3. iScience. 2022 Oct 21. 25(10): 105190
    Link between glucose metabolism and epithelial-to-mesenchymal transition drives triple-negative breast cancer migratory heterogeneity.
    Samantha C Schwager, Jenna A Mosier, Reethi S Padmanabhan, Addison White, Qinzhe Xing, Lauren A Hapach, Paul V Taufalele, Ismael Ortiz, Cynthia A Reinhart-King.
      Intracellular and environmental cues result in heterogeneous cancer cell populations with different metabolic and migratory behaviors. Although glucose metabolism and epithelial-to-mesenchymal transition have previously been linked, we aim to understand how this relationship fuels cancer cell migration. We show that while glycolysis drives single-cell migration in confining microtracks, fast and slow cells display different migratory sensitivities to glycolysis and oxidative phosphorylation inhibition. Phenotypic sorting of highly and weakly migratory subpopulations (MDA+, MDA-) reveals that more mesenchymal, highly migratory MDA+ preferentially use glycolysis while more epithelial, weakly migratory MDA- utilize mitochondrial respiration. These phenotypes are plastic and MDA+ can be made less glycolytic, mesenchymal, and migratory and MDA- can be made more glycolytic, mesenchymal, and migratory via modulation of glucose metabolism or EMT. These findings reveal an intrinsic link between EMT and glucose metabolism that controls migration. Identifying mechanisms fueling phenotypic heterogeneity is essential to develop targeted metastatic therapeutics.
    Keywords:  Biological sciences; cancer; human metabolism; physiology
    DOI:  https://doi.org/10.1016/j.isci.2022.105190
  4. EMBO Mol Med. 2022 Oct 24. e15343
    Lactate dehydrogenases promote glioblastoma growth and invasion via a metabolic symbiosis.
    Joris Guyon, Ignacio Fernandez-Moncada, Claire M Larrieu, Cyrielle L Bouchez, Antonio C Pagano Zottola, Johanna Galvis, Tiffanie Chouleur, Audrey Burban, Kevin Joseph, Vidhya M Ravi, Heidi Espedal, Gro Vatne Røsland, Boutaina Daher, Aurélien Barre, Benjamin Dartigues, Slim Karkar, Justine Rudewicz, Irati Romero-Garmendia, Barbara Klink, Konrad Grützmann, Marie-Alix Derieppe, Thibaut Molinié, Nina Obad, Céline Léon, Giorgio Seano, Hrvoje Miletic, Dieter Henrik Heiland, Giovanni Marsicano, Macha Nikolski, Rolf Bjerkvig, Andreas Bikfalvi, Thomas Daubon.
      Lactate is a central metabolite in brain physiology but also contributes to tumor development. Glioblastoma (GB) is the most common and malignant primary brain tumor in adults, recognized by angiogenic and invasive growth, in addition to its altered metabolism. We show herein that lactate fuels GB anaplerosis by replenishing the tricarboxylic acid (TCA) cycle in absence of glucose. Lactate dehydrogenases (LDHA and LDHB), which we found spatially expressed in GB tissues, catalyze the interconversion of pyruvate and lactate. However, ablation of both LDH isoforms, but not only one, led to a reduction in tumor growth and an increase in mouse survival. Comparative transcriptomics and metabolomics revealed metabolic rewiring involving high oxidative phosphorylation (OXPHOS) in the LDHA/B KO group which sensitized tumors to cranial irradiation, thus improving mouse survival. When mice were treated with the antiepileptic drug stiripentol, which targets LDH activity, tumor growth decreased. Our findings unveil the complex metabolic network in which both LDHA and LDHB are integrated and show that the combined inhibition of LDHA and LDHB strongly sensitizes GB to therapy.
    Keywords:  antiepileptic drug; energy metabolism; glioblastoma; invasion; lactate dehydrogenases
    DOI:  https://doi.org/10.15252/emmm.202115343
  5. Nat Commun. 2022 Oct 23. 13(1): 6308
    Metabolic control of CD47 expression through LAT2-mediated amino acid uptake promotes tumor immune evasion.
    Zenan Wang, Binghao Li, Shan Li, Wenlong Lin, Zhan Wang, Shengdong Wang, Weida Chen, Wei Shi, Tao Chen, Hao Zhou, Eloy Yinwang, Wenkan Zhang, Haochen Mou, Xupeng Chai, Jiahao Zhang, Zhimin Lu, Zhaoming Ye.
      Chemotherapy elicits tumor immune evasion with poorly characterized mechanisms. Here, we demonstrate that chemotherapy markedly enhances the expression levels of CD47 in osteosarcoma tissues, which are positively associated with patient mortality. We reveal that macrophages in response to chemotherapy secrete interleukin-18, which in turn upregulates expression of L-amino acid transporter 2 (LAT2) in tumor cells for substantially enhanced uptakes of leucine and glutamine, two potent stimulators of mTORC1. The increased levels of leucine and enhanced glutaminolysis activate mTORC1 and subsequent c-Myc-mediated transcription of CD47. Depletion of LAT2 or treatment of tumor cells with a LAT inhibitor downregulates CD47 with enhanced macrophage infiltration and phagocytosis of tumor cells, and sensitizes osteosarcoma to doxorubicin treatment in mice. These findings unveil a mutual regulation between macrophage and tumor cells that plays a critical role in tumor immune evasion and underscore the potential to intervene with the LAT2-mediated amino acid uptake for improving cancer therapies.
    DOI:  https://doi.org/10.1038/s41467-022-34064-4
  6. Cell Death Dis. 2022 Oct 27. 13(10): 906
    Limiting glutamine utilization activates a GCN2/TRAIL-R2/Caspase-8 apoptotic pathway in glutamine-addicted tumor cells.
    Rosario Yerbes, Rocío Mora-Molina, F Javier Fernández-Farrán, Laura Hiraldo, Abelardo López-Rivas, Carmen Palacios.
      Oncogenic transformation leads to changes in glutamine metabolism that make transformed cells highly dependent on glutamine for anabolic growth and survival. Herein, we investigated the cell death mechanism activated in glutamine-addicted tumor cells in response to the limitation of glutamine metabolism. We show that glutamine starvation triggers a FADD and caspase-8-dependent and mitochondria-operated apoptotic program in tumor cells that involves the pro-apoptotic TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2), but is independent of its cognate ligand TRAIL. In glutamine-depleted tumor cells, activation of the amino acid-sensing general control nonderepressible-2 kinase (GCN2) is responsible for TRAIL-R2 upregulation, caspase-8 activation, and apoptotic cell death. Interestingly, GCN2-dependent ISR signaling induced by methionine starvation also leads to TRAIL-R2 upregulation and apoptosis. Moreover, pharmacological inhibition of transaminases activates a GCN2 and TRAIL-R2-dependent apoptotic mechanism that is inhibited by non-essential amino acids (NEAA). In addition, metabolic stress upon glutamine deprivation also results in GCN2-independent FLICE-inhibitory protein (FLIP) downregulation facilitating caspase-8 activation and apoptosis. Importantly, downregulation of the long FLIP splice form (FLIPL) and apoptosis upon glutamine deprivation are inhibited in the presence of a membrane-permeable α-ketoglutarate. Collectively, our data support a model in which limiting glutamine utilization in glutamine-addicted tumor cells triggers a previously unknown cell death mechanism regulated by GCN2 that involves the TRAIL-R2-mediated activation of the extrinsic apoptotic pathway.
    DOI:  https://doi.org/10.1038/s41419-022-05346-y
  7. Subcell Biochem. 2022 ;100 143-172
    Autophagy in Cancer: A Metabolic Perspective.
    Sweta Sikder, Atanu Mondal, Chandrima Das, Tapas K Kundu.
      Autophagy is an intracellular catabolic degradative process in which damaged cellular organelles, unwanted proteins and different cytoplasmic components get recycled to maintain cellular homeostasis or metabolic balance. During autophagy, a double membrane vesicle is formed to engulf these cytosolic materials and fuse to lysosomes wherein the entire cargo degrades to be used again. Because of this unique recycling ability of cells, autophagy is a universal stress response mechanism. Dysregulation of autophagy leads to several diseases, including cancer, neurodegeneration and microbial infection. Thus, autophagy machineries have become targets for therapeutics. This chapter provides an overview of the paradoxical role of autophagy in tumorigenesis in the perspective of metabolism.
    Keywords:  Autophagy; Cancer; Histone modifications; Metabolism
    DOI:  https://doi.org/10.1007/978-3-031-07634-3_5
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