bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2022–10–23
eight papers selected by
Linda Chan, Yale University
  1. Metabolic guidance and stress in tumors modulate antigen-presenting cells.
  2. Rerouting the drug response: Overcoming metabolic adaptation in KRAS-mutant cancers.
  3. Tumor-produced and aging-associated oncometabolite methylmalonic acid promotes cancer-associated fibroblast activation to drive metastatic progression.
  4. Deregulated transcription factors in cancer cell metabolisms and reprogramming.
  5. The role of lipids in cancer progression and metastasis.
  6. Methionine uptake via the SLC43A2 transporter is essential for regulatory T-cell survival.
  7. SUSD2 suppresses CD8+ T cell antitumor immunity by targeting IL-2 receptor signaling.
  8. Single-cell sequencing reveals effects of chemotherapy on the immune landscape and TCR/BCR clonal expansion in a relapsed ovarian cancer patient.
  1. Oncogenesis. 2022 Oct 16. 11(1): 62
    Metabolic guidance and stress in tumors modulate antigen-presenting cells.
    Jaeoh Park, Limei Wang, Ping-Chih Ho.
      Successful antitumor immunity largely relies on efficient T cell priming by antigen-presenting cells (APCs); however, the capacity of APCs is found to be defective in many cancers. Metabolically reprogrammed cancer cells support the energetic and biosynthetic demands of their high proliferation rates by exploiting nutrients available in the tumor microenvironment (TME), which in turn limits proper metabolic reprogramming of APCs during recruitment, differentiation, activation and antigen presentation. Furthermore, some metabolites generated by the TME are unfavorable to antitumor immunity. This review summarizes recent studies on the metabolic features of APCs and their functionality in the TME. Particularly, we will describe how APCs respond to altered TME and how metabolic byproducts from cancer and immunomodulatory cells affect APCs. Finally, we introduce the current status of APC-oriented research and clinical trials targeting metabolic features to boost efficient immunotherapy.
    DOI:  https://doi.org/10.1038/s41389-022-00438-y
  2. Sci Signal. 2022 Oct 18. 15(756): eabj3490
    Rerouting the drug response: Overcoming metabolic adaptation in KRAS-mutant cancers.
    Deborah Y Moss, Christopher McCann, Emma M Kerr.
      Mutations in guanosine triphosphatase KRAS are common in lung, colorectal, and pancreatic cancers. The constitutive activity of mutant KRAS and its downstream signaling pathways induces metabolic rewiring in tumor cells that can promote resistance to existing therapeutics. In this review, we discuss the metabolic pathways that are altered in response to treatment and those that can, in turn, alter treatment efficacy, as well as the role of metabolism in the tumor microenvironment (TME) in dictating the therapeutic response in KRAS-driven cancers. We highlight metabolic targets that may provide clinical opportunities to overcome therapeutic resistance and improve survival in patients with these aggressive cancers.
    DOI:  https://doi.org/10.1126/scisignal.abj3490
  3. Nat Commun. 2022 Oct 20. 13(1): 6239
    Tumor-produced and aging-associated oncometabolite methylmalonic acid promotes cancer-associated fibroblast activation to drive metastatic progression.
    Zhongchi Li, Vivien Low, Valbona Luga, Janet Sun, Ethan Earlie, Bobak Parang, Kripa Shobana Ganesh, Sungyun Cho, Jennifer Endress, Tanya Schild, Mengying Hu, David Lyden, Wenbing Jin, Chunjun Guo, Noah Dephoure, Lewis C Cantley, Ashley M Laughney, John Blenis.
      The systemic metabolic shifts that occur during aging and the local metabolic alterations of a tumor, its stroma and their communication cooperate to establish a unique tumor microenvironment (TME) fostering cancer progression. Here, we show that methylmalonic acid (MMA), an aging-increased oncometabolite also produced by aggressive cancer cells, activates fibroblasts in the TME, which reciprocally secrete IL-6 loaded extracellular vesicles (EVs) that drive cancer progression, drug resistance and metastasis. The cancer-associated fibroblast (CAF)-released EV cargo is modified as a result of reactive oxygen species (ROS) generation and activation of the canonical and noncanonical TGFβ signaling pathways. EV-associated IL-6 functions as a stroma-tumor messenger, activating the JAK/STAT3 and TGFβ signaling pathways in tumor cells and promoting pro-aggressive behaviors. Our findings define the role of MMA in CAF activation to drive metastatic reprogramming, unveiling potential therapeutic avenues to target MMA at the nexus of aging, the tumor microenvironment and metastasis.
    DOI:  https://doi.org/10.1038/s41467-022-33862-0
  4. Semin Cancer Biol. 2022 Oct 13. pii: S1044-579X(22)00205-X. [Epub ahead of print]
    Deregulated transcription factors in cancer cell metabolisms and reprogramming.
    Rajni Kant, Rajesh Kumar Manne, Mohammad Anas, Vasudevarao Penugurti, Tingjin Chen, Bo-Syong Pan, Che-Chia Hsu, Hui-Kuan Lin.
      Metabolic reprogramming is an important cancer hallmark that plays a key role in cancer malignancies and therapy resistance. Cancer cells reprogram the metabolic pathways to generate not only energy and building blocks but also produce numerous key signaling metabolites to impact signaling and epigenetic/transcriptional regulation for cancer cell proliferation and survival. A deeper understanding of the mechanisms by which metabolic reprogramming is regulated in cancer may provide potential new strategies for cancer targeting. Recent studies suggest that deregulated transcription factors have been observed in various human cancers and significantly impact metabolism and signaling in cancer. In this review, we highlight the key transcription factors that are involved in metabolic control, dissect the crosstalk between signaling and transcription factors in metabolic reprogramming, and offer therapeutic strategies targeting deregulated transcription factors for cancer treatment.
    Keywords:  Cancer treatment; Cell metabolism; Metabolic Reprogramming; Transcription Factors; signaling metabolites
    DOI:  https://doi.org/10.1016/j.semcancer.2022.10.001
  5. Cell Metab. 2022 Oct 14. pii: S1550-4131(22)00447-8. [Epub ahead of print]
    The role of lipids in cancer progression and metastasis.
    Miguel Martin-Perez, Uxue Urdiroz-Urricelqui, Claudia Bigas, Salvador Aznar Benitah.
      Lipids have essential biological functions in the body (e.g., providing energy storage, acting as a signaling molecule, and being a structural component of membranes); however, an excess of lipids can promote tumorigenesis, colonization, and metastatic capacity of tumor cells. To metastasize, a tumor cell goes through different stages that require lipid-related metabolic and structural adaptations. These adaptations include altering the lipid membrane composition for invading other niches and overcoming cell death mechanisms and promoting lipid catabolism and anabolism for energy and oxidative stress protective purposes. Cancer cells also harness lipid metabolism to modulate the activity of stromal and immune cells to their advantage and to resist therapy and promote relapse. All this is especially worrying given the high fat intake in Western diets. Thus, metabolic interventions aiming to reduce lipid availability to cancer cells or to exacerbate their metabolic vulnerabilities provide promising therapeutic opportunities to prevent cancer progression and treat metastasis.
    Keywords:  lipid metabolism; metastasis; metastatic-initiating cells; tumor storm
    DOI:  https://doi.org/10.1016/j.cmet.2022.09.023
  6. Life Sci Alliance. 2022 Dec;pii: e202201663. [Epub ahead of print]5(12):
    Methionine uptake via the SLC43A2 transporter is essential for regulatory T-cell survival.
    Neetu Saini, Afsana Naaz, Shree Padma Metur, Pinki Gahlot, Adhish Walvekar, Anupam Dutta, Umamaheswari Davathamizhan, Apurva Sarin, Sunil Laxman.
      Cell death, survival, or growth decisions in T-cell subsets depend on interplay between cytokine-dependent and metabolic processes. The metabolic requirements of T-regulatory cells (Tregs) for their survival and how these are satisfied remain unclear. Herein, we identified a necessary requirement of methionine uptake and usage for Tregs survival upon IL-2 deprivation. Activated Tregs have high methionine uptake and usage to S-adenosyl methionine, and this uptake is essential for Tregs survival in conditions of IL-2 deprivation. We identify a solute carrier protein SLC43A2 transporter, regulated in a Notch1-dependent manner that is necessary for this methionine uptake and Tregs viability. Collectively, we uncover a specifically regulated mechanism of methionine import in Tregs that is required for cells to adapt to cytokine withdrawal. We highlight the need for methionine availability and metabolism in contextually regulating cell death in this immunosuppressive population of T cells.
    DOI:  https://doi.org/10.26508/lsa.202201663
  7. Nat Immunol. 2022 Oct 20.
    SUSD2 suppresses CD8+ T cell antitumor immunity by targeting IL-2 receptor signaling.
    Bao Zhao, Weipeng Gong, Anjun Ma, Jianwen Chen, Maria Velegraki, Hong Dong, Zihao Liu, Lingling Wang, Tamio Okimoto, Devin M Jones, Yu L Lei, Meixiao Long, Kenneth J Oestreich, Qin Ma, Gang Xin, David P Carbone, Kai He, Zihai Li, Haitao Wen.
      Dysfunctional CD8+ T cells, which have defective production of antitumor effectors, represent a major mediator of immunosuppression in the tumor microenvironment. Here, we show that SUSD2 is a negative regulator of CD8+ T cell antitumor function. Susd2-/- effector CD8+ T cells showed enhanced production of antitumor molecules, which consequently blunted tumor growth in multiple syngeneic mouse tumor models. Through a quantitative mass spectrometry assay, we found that SUSD2 interacted with interleukin (IL)-2 receptor α through sushi domain-dependent protein interactions and that this interaction suppressed the binding of IL-2, an essential cytokine for the effector functions of CD8+ T cells, to IL-2 receptor α. SUSD2 was not expressed on regulatory CD4+ T cells and did not affect the inhibitory function of these cells. Adoptive transfer of Susd2-/- chimeric antigen receptor T cells induced a robust antitumor response in mice, highlighting the potential of SUSD2 as an immunotherapy target for cancer.
    DOI:  https://doi.org/10.1038/s41590-022-01326-8
  8. Front Immunol. 2022 ;13 985187
    Single-cell sequencing reveals effects of chemotherapy on the immune landscape and TCR/BCR clonal expansion in a relapsed ovarian cancer patient.
    Yanyu Ren, Runrong Li, Hanxiao Feng, Jieying Xie, Lin Gao, Shuai Chu, Yan Li, Fanliang Meng, Yunshan Ning.
      Cancer recurrence and chemoresistance are the leading causes of death in high-grade serous ovarian cancer (HGSOC) patients. However, the unique role of the immune environment in tumor progression for relapsed chemo-resistant patients remains elusive. In single-cell resolution, we characterized a comprehensive multi-dimensional cellular and immunological atlas from tumor, ascites, and peripheral blood of a chemo-resistant patient at different stages of treatment. Our results highlight a role in recurrence and chemoresistance of the immunosuppressive microenvironment in ascites, including MDSC-like myeloid and hypo-metabolic γδT cells, and of peripheral CD8+ effector T cells with chemotherapy-induced senescent/exhaustive. Importantly, paired TCR/BCR sequencing demonstrated relative conservation of TCR clonal expansion in hyper-expanded CD8+ T cells and extensive BCR clonal expansion without usage bias of V(D)J genes after chemotherapy. Thus, our study suggests strategies for ameliorating chemotherapy-induced immune impairment to improve the clinical outcome of HGSOC.
    Keywords:  TCR/BCR repertoire; chemotherapy; clonal expansion; immune microenvironment; ovarian cancer; single-cell sequencing
    DOI:  https://doi.org/10.3389/fimmu.2022.985187
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