bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2024–07–07
eight papers selected by
Oltea Sampetrean, Keio University
  1. Editorial: Double-edged swords: important factors connecting metabolic disorders and cancer development - from basic research to translational applications, volume II.
  2. Inhibition of glutamine metabolism: acting on tumoral cells or on tumor microenvironment?
  3. Amino acid metabolic reprogramming in the tumor microenvironment and its implication for cancer therapy.
  4. Interactions of Fatty Acid and Cholesterol Metabolism with Cellular Stress Response Pathways in Cancer.
  5. The significance of lipid metabolism reprogramming of tumor-associated macrophages in hepatocellular carcinoma.
  6. Genetically engineering glycolysis in T cells increases their antitumor function.
  7. Identification of Hypoxia-ALCAMhigh Macrophage- Exhausted T Cell Axis in Tumor Microenvironment Remodeling for Immunotherapy Resistance.
  8. Metabolic crosstalk: Extracellular ATP and the tumor microenvironment in cancer progression and therapy.
  1. Front Endocrinol (Lausanne). 2024 ;15 1441828
    Editorial: Double-edged swords: important factors connecting metabolic disorders and cancer development - from basic research to translational applications, volume II.
    Che-Pei Kung, Thibaut Barnoud, Cong-Hui Yao, Irene Bertolini, Maureen E Murphy.
      
    Keywords:  basic research; cancer; metabolic disorder; metabolism; translational research
    DOI:  https://doi.org/10.3389/fendo.2024.1441828
  2. Oncotarget. 2023 Aug 10. 14 755-757
    Inhibition of glutamine metabolism: acting on tumoral cells or on tumor microenvironment?
    Raul Peña.
      
    Keywords:  CAF; fibroblasts; glutamine; snail1; tumor microenvironment
    DOI:  https://doi.org/10.18632/oncotarget.28443
  3. J Cell Physiol. 2024 Jun 30.
    Amino acid metabolic reprogramming in the tumor microenvironment and its implication for cancer therapy.
    Jiarong Zhang, Mingjian Chen, Yuxin Yang, Ziqi Liu, Wanni Guo, Pingjuan Xiang, Zhaoyang Zeng, Dan Wang, Wei Xiong.
      Amino acids are essential building blocks for proteins, crucial energy sources for cell survival, and key signaling molecules supporting the resistant growth of tumor cells. In tumor cells, amino acid metabolic reprogramming is characterized by the enhanced uptake of amino acids as well as their aberrant synthesis, breakdown, and transport, leading to immune evasion and malignant progression of tumor cells. This article reviews the altered amino acid metabolism in tumor cells and its impact on tumor microenvironment, and also provides an overview of the current clinical applications of amino acid metabolism. Innovative drugs targeting amino acid metabolism hold great promise for precision and personalized cancer therapy.
    Keywords:  amino acid metabolism; immune evasion; metabolic reprogramming; tumor microenvironment; tumor resistance
    DOI:  https://doi.org/10.1002/jcp.31349
  4. Cold Spring Harb Perspect Med. 2024 Jul 01. pii: a041548. [Epub ahead of print]
    Interactions of Fatty Acid and Cholesterol Metabolism with Cellular Stress Response Pathways in Cancer.
    Alina M Winkelkotte, Kamal Al-Shami, Adriano B Chaves-Filho, Felix C E Vogel, Almut Schulze.
      Lipids have essential functions as structural components of cellular membranes, as efficient energy storage molecules, and as precursors of signaling mediators. While deregulated glucose and amino acid metabolism in cancer have received substantial attention, the roles of lipids in the metabolic reprogramming of cancer cells are less well understood. However, since the first description of de novo fatty acid biosynthesis in cancer tissues almost 70 years ago, numerous studies have investigated the complex functions of altered lipid metabolism in cancer. Here, we will summarize the mechanisms by which oncogenic signaling pathways regulate fatty acid and cholesterol metabolism to drive rapid proliferation and protect cancer cells from environmental stress. The review also discusses the role of fatty acid metabolism in metabolic plasticity required for the adaptation to changing microenvironments during cancer progression and the connections between fatty acid and cholesterol metabolism and ferroptosis.
    DOI:  https://doi.org/10.1101/cshperspect.a041548
  5. Cancer Immunol Immunother. 2024 Jul 02. 73(9): 171
    The significance of lipid metabolism reprogramming of tumor-associated macrophages in hepatocellular carcinoma.
    Qingjian Xie, Yuan Zeng, Xiangting Zhang, Fujun Yu.
      In the intricate landscape of the tumor microenvironment, tumor-associated macrophages (TAMs) emerge as a ubiquitous cellular component that profoundly affects the oncogenic process. The microenvironment of hepatocellular carcinoma (HCC) is characterized by a pronounced infiltration of TAMs, underscoring their pivotal role in modulating the trajectory of the disease. Amidst the evolving therapeutic paradigms for HCC, the strategic reprogramming of metabolic pathways presents a promising avenue for intervention, garnering escalating interest within the scientific community. Previous investigations have predominantly focused on elucidating the mechanisms of metabolic reprogramming in cancer cells without paying sufficient attention to understanding how TAM metabolic reprogramming, particularly lipid metabolism, affects the progression of HCC. In this review article, we intend to elucidate how TAMs exert their regulatory effects via diverse pathways such as E2F1-E2F2-CPT2, LKB1-AMPK, and mTORC1-SREBP, and discuss correlations of TAMs with these processes and the characteristics of relevant pathways in HCC progression by consolidating various studies on TAM lipid uptake, storage, synthesis, and catabolism. It is our hope that our summary could delineate the impact of specific mechanisms underlying TAM lipid metabolic reprogramming on HCC progression and provide useful information for future research on HCC and the development of new treatment strategies.
    Keywords:  Hepatocellular carcinoma; Lipid metabolic reprogramming; Tumor microenvironments; Tumor-associated macrophages
    DOI:  https://doi.org/10.1007/s00262-024-03748-9
  6. J Immunother Cancer. 2024 Jul 04. pii: e008434. [Epub ahead of print]12(7):
    Genetically engineering glycolysis in T cells increases their antitumor function.
    Raphaëlle Toledano Zur, Orna Atar, Tilda Barliya, Shiran Hoogi, Ifat Abramovich, Eyal Gottlieb, Noga Ron-Harel, Cyrille J Cohen.
       BACKGROUND: T cells play a central role in the antitumor response. However, they often face numerous hurdles in the tumor microenvironment, including the scarcity of available essential metabolites such as glucose and amino acids. Moreover, cancer cells can monopolize these resources to thrive and proliferate by upregulating metabolite transporters and maintaining a high metabolic rate, thereby outcompeting T cells.
    METHODS: Herein, we sought to improve T-cell antitumor function in the tumor vicinity by enhancing their glycolytic capacity to better compete with tumor cells. To achieve this, we engineered human T cells to express a key glycolysis enzyme, phosphofructokinase, in conjunction with Glucose transporter 3, a glucose transporter. We co-expressed these, along with tumor-specific chimeric antigen or T-cell receptors.
    RESULTS: Engineered cells demonstrated an increased cytokine secretion and upregulation of T-cell activation markers compared with control cells. Moreover, they displayed superior glycolytic capacity, which translated into an improved in vivo therapeutic potential in a xenograft model of human tumors.
    CONCLUSION: In summary, these findings support the implementation of T-cell metabolic engineering to enhance the efficacy of cellular immunotherapies for cancer.
    Keywords:  Immunotherapy; Receptors, Antigen; T-Lymphocytes
    DOI:  https://doi.org/10.1136/jitc-2023-008434
  7. Adv Sci (Weinh). 2024 Jul 02. e2309885
    Identification of Hypoxia-ALCAMhigh Macrophage- Exhausted T Cell Axis in Tumor Microenvironment Remodeling for Immunotherapy Resistance.
    Zhenzhen Xun, Huanran Zhou, Mingyi Shen, Yao Liu, Chengcao Sun, Yanhua Du, Zhou Jiang, Liuqing Yang, Qing Zhang, Chunru Lin, Qingsong Hu, Youqiong Ye, Leng Han.
      Although hypoxia is known to be associated with immune resistance, the adaptability to hypoxia by different cell populations in the tumor microenvironment and the underlying mechanisms remain elusive. This knowledge gap has hindered the development of therapeutic strategies to overcome tumor immune resistance induced by hypoxia. Here, bulk, single-cell, and spatial transcriptomics are integrated to characterize hypoxia associated with immune escape during carcinogenesis and reveal a hypoxia-based intercellular communication hub consisting of malignant cells, ALCAMhigh macrophages, and exhausted CD8+ T cells around the tumor boundary. A hypoxic microenvironment promotes binding of HIF-1α complex is demonstrated to the ALCAM promoter therefore increasing its expression in macrophages, and the ALCAMhigh macrophages co-localize with exhausted CD8+ T cells in the tumor spatial microenvironment and promote T cell exhaustion. Preclinically, HIF-1ɑ inhibition reduces ALCAM expression in macrophages and exhausted CD8+ T cells and potentiates T cell antitumor function to enhance immunotherapy efficacy. This study reveals the systematic landscape of hypoxia at single-cell resolution and spatial architecture and highlights the effect of hypoxia on immunotherapy resistance through the ALCAMhigh macrophage-exhausted T cell axis, providing a novel immunotherapeutic strategy to overcome hypoxia-induced resistance in cancers.
    Keywords:  ALCAM+ macrophage; cancer immunotherapy; exhausted T cell; hypoxia; spatial transcriptomics
    DOI:  https://doi.org/10.1002/advs.202309885
  8. Cell Signal. 2024 Jun 28. pii: S0898-6568(24)00249-3. [Epub ahead of print] 111281
    Metabolic crosstalk: Extracellular ATP and the tumor microenvironment in cancer progression and therapy.
    Sourav Shukla, Parameswar Dalai, Reena Agrawal-Rajput.
      Adenosine 5'-triphosphate (ATP) is a vital element in energy information. It plays a critical role in transmitting signals inside the body, which is necessary for controlling the life activities of all cells, including tumor cells [1]. Its significance extends from intracellular signaling pathways to tumor regression. Purinergic signaling, a form of extracellular paracrine signaling, relies on purine nucleotides. Extracellular ectonucleotidases convert these purine nucleotides to their respective di and mono-phosphate nucleoside forms, contributing significantly to immune biology, cancer biology, and inflammation studies. ATP functions as a mighty damage-linked molecular pattern when released outside the cell, accumulating in inflammatory areas. In the tumor microenvironment (TME), purinergic receptors such as ATP-gated ion channels P2X1-5 and G protein-coupled receptors (GPCR) (P2Y) interact with ATP and other nucleotides, influencing diverse immune cell activities. CD39 and CD73-mediated extracellular ATP degradation contributes to immunosuppression by diminishing ATP-dependent activation and generating adenosine (ADO), potentially hindering antitumor immunity and promoting tumor development. Unraveling the complexities of extracellular ATP (e-ATP) and ADO effects on the TME poses challenges in identifying optimal treatment targets, yet ongoing investigations aim to devise strategies combating e-ATP/ADO-induced immunosuppression, ultimately enhancing anti-tumor immunity. This review explores e-ATP metabolism, its purinergic signaling, and therapeutic strategies targeting associated receptors and enzymes.
    Keywords:  Extracellular ATP (e-ATP); Immunosuppression; Purinergic receptors; Purinergic signaling; Therapeutic potential; Tumor microenvironment (TME)
    DOI:  https://doi.org/10.1016/j.cellsig.2024.111281
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