bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2023–09–03
six papers selected by
Oltea Sampetrean, Keio University
  1. Metabolic partitioning in the brain and its hijacking by glioblastoma.
  2. Formate promotes invasion and metastasis in reliance on lipid metabolism.
  3. Molecular, metabolic, and functional CD4 T cell paralysis in the lymph node impedes tumor control.
  4. Metabolic programs of T cell tissue residency empower tumour immunity.
  5. Lipid metabolic vulnerabilities of multiple myeloma.
  6. Adipocytes reprogram cancer cell metabolism by diverting glucose towards glycerol-3-phosphate thereby promoting metastasis.
  1. Genes Dev. 2023 Aug 30.
    Metabolic partitioning in the brain and its hijacking by glioblastoma.
    Jed de Ruiter Swain, Evdokia Michalopoulou, Evan K Noch, Michael J Lukey, Linda Van Aelst.
      The different cell types in the brain have highly specialized roles with unique metabolic requirements. Normal brain function requires the coordinated partitioning of metabolic pathways between these cells, such as in the neuron-astrocyte glutamate-glutamine cycle. An emerging theme in glioblastoma (GBM) biology is that malignant cells integrate into or "hijack" brain metabolism, co-opting neurons and glia for the supply of nutrients and recycling of waste products. Moreover, GBM cells communicate via signaling metabolites in the tumor microenvironment to promote tumor growth and induce immune suppression. Recent findings in this field point toward new therapeutic strategies to target the metabolic exchange processes that fuel tumorigenesis and suppress the anticancer immune response in GBM. Here, we provide an overview of the intercellular division of metabolic labor that occurs in both the normal brain and the GBM tumor microenvironment and then discuss the implications of these interactions for GBM therapy.
    Keywords:  IDH mutation; brain metabolism; cancer metabolism; glioblastoma; glioma; glioma therapy; immune suppression; tumor microenvironment
    DOI:  https://doi.org/10.1101/gad.350693.123
  2. Cell Rep. 2023 Aug 30. pii: S2211-1247(23)01045-8. [Epub ahead of print]42(9): 113034
    Formate promotes invasion and metastasis in reliance on lipid metabolism.
    Catherine Delbrouck, Nicole Kiweler, Oleg Chen, Vitaly I Pozdeev, Lara Haase, Laura Neises, Anaïs Oudin, Aymeric Fouquier d'Hérouël, Ruolin Shen, Lisa Schlicker, Rashi Halder, Antoine Lesur, Anne Schuster, Nadja I Lorenz, Christian Jaeger, Maureen Feucherolles, Gilles Frache, Martyna Szpakowska, Andy Chevigne, Michael W Ronellenfitsch, Etienne Moussay, Marie Piraud, Alexander Skupin, Almut Schulze, Simone P Niclou, Elisabeth Letellier, Johannes Meiser.
      Metabolic rewiring is essential for cancer onset and progression. We previously showed that one-carbon metabolism-dependent formate production often exceeds the anabolic demand of cancer cells, resulting in formate overflow. Furthermore, we showed that increased extracellular formate concentrations promote the in vitro invasiveness of glioblastoma cells. Here, we substantiate these initial observations with ex vivo and in vivo experiments. We also show that exposure to exogeneous formate can prime cancer cells toward a pro-invasive phenotype leading to increased metastasis formation in vivo. Our results suggest that the increased local formate concentration within the tumor microenvironment can be one factor to promote metastases. Additionally, we describe a mechanistic interplay between formate-dependent increased invasiveness and adaptations of lipid metabolism and matrix metalloproteinase activity. Our findings consolidate the role of formate as pro-invasive metabolite and warrant further research to better understand the interplay between formate and lipid metabolism.
    Keywords:  CP: Cancer; CP: Metabolism; cancer metastasis; formate overflow; invasion; one-carbon metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2023.113034
  3. Cell Rep. 2023 Aug 30. pii: S2211-1247(23)01058-6. [Epub ahead of print]42(9): 113047
    Molecular, metabolic, and functional CD4 T cell paralysis in the lymph node impedes tumor control.
    Mengdi Guo, Diala Abd-Rabbo, Bruna C Bertol, Madeleine Carew, Sabelo Lukhele, Laura M Snell, Wenxi Xu, Giselle M Boukhaled, Heidi Elsaesser, Marie Jo Halaby, Naoto Hirano, Tracy L McGaha, David G Brooks.
      CD4 T cells are central effectors of anti-cancer immunity and immunotherapy, yet the regulation of CD4 tumor-specific T (TTS) cells is unclear. We demonstrate that CD4 TTS cells are quickly primed and begin to divide following tumor initiation. However, unlike CD8 TTS cells or exhaustion programming, CD4 TTS cell proliferation is rapidly frozen in place by a functional interplay of regulatory T cells and CTLA4. Together these mechanisms paralyze CD4 TTS cell differentiation, redirecting metabolic circuits, and reducing their accumulation in the tumor. The paralyzed state is actively maintained throughout cancer progression and CD4 TTS cells rapidly resume proliferation and functional differentiation when the suppressive constraints are alleviated. Overcoming their paralysis established long-term tumor control, demonstrating the importance of rapidly crippling CD4 TTS cells for tumor progression and their potential restoration as therapeutic targets.
    Keywords:  CD4 T cell; CP: Immunology; CTLA4; T regulatory cell; cancer; dysfunction; exhaustion; immunotherapy; metabolism; transcriptomic signature; tumor immunology
    DOI:  https://doi.org/10.1016/j.celrep.2023.113047
  4. Nature. 2023 Aug 30.
    Metabolic programs of T cell tissue residency empower tumour immunity.
    Miguel Reina-Campos, Maximilian Heeg, Kelly Kennewick, Ian T Mathews, Giovanni Galletti, Vida Luna, Quynhanh Nguyen, Hongling Huang, J Justin Milner, Kenneth H Hu, Amy Vichaidit, Natalie Santillano, Brigid S Boland, John T Chang, Mohit Jain, Sonia Sharma, Matthew F Krummel, Hongbo Chi, Steven J Bensinger, Ananda W Goldrath.
      Tissue resident memory CD8+ T (TRM) cells offer rapid and long-term protection at sites of reinfection1. Tumour-infiltrating lymphocytes with characteristics of TRM cells maintain enhanced effector functions, predict responses to immunotherapy and accompany better prognoses2,3. Thus, an improved understanding of the metabolic strategies that enable tissue residency by T cells could inform new approaches to empower immune responses in tissues and solid tumours. Here, to systematically define the basis for the metabolic reprogramming supporting TRM cell differentiation, survival and function, we leveraged in vivo functional genomics, untargeted metabolomics and transcriptomics of virus-specific memory CD8+ T cell populations. We found that memory CD8+ T cells deployed a range of adaptations to tissue residency, including reliance on non-steroidal products of the mevalonate-cholesterol pathway, such as coenzyme Q, driven by increased activity of the transcription factor SREBP2. This metabolic adaptation was most pronounced in the small intestine, where TRM cells interface with dietary cholesterol and maintain a heightened state of activation4, and was shared by functional tumour-infiltrating lymphocytes in diverse tumour types in mice and humans. Enforcing synthesis of coenzyme Q through deletion of Fdft1 or overexpression of PDSS2 promoted mitochondrial respiration, memory T cell formation following viral infection and enhanced antitumour immunity. In sum, through a systematic exploration of TRM cell metabolism, we reveal how these programs can be leveraged to fuel memory CD8+ T cell formation in the context of acute infections and enhance antitumour immunity.
    DOI:  https://doi.org/10.1038/s41586-023-06483-w
  5. Clin Exp Med. 2023 Aug 28.
    Lipid metabolic vulnerabilities of multiple myeloma.
    Roberta Torcasio, Maria Eugenia Gallo Cantafio, Raissa Kaori Ikeda, Ludovica Ganino, Giuseppe Viglietto, Nicola Amodio.
      Multiple myeloma (MM) is the second most common hematological malignancy worldwide, characterized by abnormal proliferation of malignant plasma cells within a tumor-permissive bone marrow microenvironment. Metabolic dysfunctions are emerging as key determinants in the pathobiology of MM. In this review, we highlight the metabolic features of MM, showing how alterations in various lipid pathways, mainly involving fatty acids, cholesterol and sphingolipids, affect the growth, survival and drug responsiveness of MM cells, as well as their cross-talk with other cellular components of the tumor microenvironment. These findings will provide a new path to understanding the mechanisms underlying how lipid vulnerabilities may arise and affect the phenotype of malignant plasma cells, highlighting novel druggable pathways with a significant impact on the management of MM.
    Keywords:  Cholesterol; Fatty acids; Lipid metabolism; Metabolic reprogramming; Multiple myeloma; Sphingolipids
    DOI:  https://doi.org/10.1007/s10238-023-01174-2
  6. Nat Metab. 2023 Aug 31.
    Adipocytes reprogram cancer cell metabolism by diverting glucose towards glycerol-3-phosphate thereby promoting metastasis.
    Abir Mukherjee, Divya Bezwada, Francesco Greco, Malu Zandbergen, Tong Shen, Chun-Yi Chiang, Medine Tasdemir, Johannes Fahrmann, Dmitry Grapov, Michael R La Frano, Hieu S Vu, Brandon Faubert, John W Newman, Liam A McDonnell, Luigi Nezi, Oliver Fiehn, Ralph J DeBerardinis, Ernst Lengyel.
      In the tumor microenvironment, adipocytes function as an alternate fuel source for cancer cells. However, whether adipocytes influence macromolecular biosynthesis in cancer cells is unknown. Here we systematically characterized the bidirectional interaction between primary human adipocytes and ovarian cancer (OvCa) cells using multi-platform metabolomics, imaging mass spectrometry, isotope tracing and gene expression analysis. We report that, in OvCa cells co-cultured with adipocytes and in metastatic tumors, a part of the glucose from glycolysis is utilized for the biosynthesis of glycerol-3-phosphate (G3P). Normoxic HIF1α protein regulates the altered flow of glucose-derived carbons in cancer cells, resulting in increased glycerophospholipids and triacylglycerol synthesis. The knockdown of HIF1α or G3P acyltransferase 3 (a regulatory enzyme of glycerophospholipid synthesis) reduced metastasis in xenograft models of OvCa. In summary, we show that, in an adipose-rich tumor microenvironment, cancer cells generate G3P as a precursor for critical membrane and signaling components, thereby promoting metastasis. Targeting biosynthetic processes specific to adipose-rich tumor microenvironments might be an effective strategy against metastasis.
    DOI:  https://doi.org/10.1038/s42255-023-00879-8
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