bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2023‒07‒23
six papers selected by
Oltea Sampetrean, Keio University
  1. How nearby nutrients shape tumor growth.
  2. Remodeling the tumor microenvironment to overcome treatment resistance in HPV-negative head and neck cancer.
  3. The immunomodulatory role of IDO1-Kynurenine-NAD+ pathway in switching cold tumor microenvironment in PDAC.
  4. Adipose tissue and skeletal muscle wasting precede clinical diagnosis of pancreatic cancer.
  5. Oncolytic viruses engineered to enforce cholesterol efflux restore tumor-associated macrophage phagocytosis and anti-tumor immunity in glioblastoma.
  6. The SLC38A5/SNAT5 amino acid transporter: from pathophysiology to pro-cancer roles in the tumor microenvironment.
  1. Elife. 2023 07 17. pii: e89825. [Epub ahead of print]12
    How nearby nutrients shape tumor growth.
    Nada Kalaany.
      Studying the nutrient composition immediately surrounding pancreatic cancer cells provides new insights into their metabolic properties and how they can evade the immune system to promote disease progression.
    Keywords:  amino acid homeostasis; biochemistry; cancer; cancer biology; chemical biology; human; immunotherapy; metabolism; mouse; nutrient stress; tumor microenvironment
    DOI:  https://doi.org/10.7554/eLife.89825
  2. Cancer Drug Resist. 2023 ;6(2): 291-313
    Remodeling the tumor microenvironment to overcome treatment resistance in HPV-negative head and neck cancer.
    Sergi Benavente.
      Despite intensive efforts and refined techniques, overall survival in HPV-negative head and neck cancer remains poor. Robust immune priming is required to elicit a strong and durable antitumor immune response in immunologically cold and excluded tumors like HPV-negative head and neck cancer. This review highlights how the tumor microenvironment could be affected by different immune and stromal cell types, weighs the need to integrate metabolic regulation of the tumor microenvironment into cancer treatment strategies and summarizes the emerging clinical applicability of personalized immunotherapeutic strategies in HPV-negative head and neck cancer.
    Keywords:  HPV-negative; SBRT; Tumor microenvironments; head and neck cancer; immunotherapy; metabolic reprogramming; radiotherapy
    DOI:  https://doi.org/10.20517/cdr.2022.141
  3. Front Oncol. 2023 ;13 1142838
    The immunomodulatory role of IDO1-Kynurenine-NAD+ pathway in switching cold tumor microenvironment in PDAC.
    R I Anu, Kai-Keen Shiu, Khurum Hayat Khan.
      Pancreatic ductal adenocarcinoma (PDAC) is the most common exocrine tumor of the pancreas characterized by late diagnosis, adverse overall 5-year survival, a higher propensity for metastatic disease, and lack of efficacy of systemic therapy options. These adverse outcomes can be partly attributed to complex tumor microenvironment (TME). Over the past decade, immunotherapy has revolutionized the management of certain cancers; thus far, the immunologically 'non-inflamed' tumor microenvironment in PDACs has proven to be challenging. Indolamine 2,3-dioxygenase 1 (IDO1) is the rate-limiting enzyme in the catabolic pathway of L-Tryptophan, an essential amino acid, that gives rise to the immunosuppressive metabolite Kynurenine. IDO1, Indolamine 2,3-dioxygenase 2 (IDO2), and Tryptophan 2,3-dioxygenase (TDO) are the key enzymes in the tryptophan catabolic pathway but we focus on the role of the predominant enzyme form IDO1 in this review. Nicotinamide phosphoribosyl transferase (iNAMPT) regulates the intracellular concentration of NAD and is upregulated in the tumor. In light of the potential role of IDO1 as a driver of hostile TME in PDAC and NAD+ as a key coenzyme in anti-tumor immune response, this review urges focus on extensive research and initiation of clinical trials using IDO1 and NAMPT inhibitors in pancreatic cancer in the future.
    Keywords:  Indolamine 2,3-dioxygenase 1; Kynurenine; NAD; NAMPT inhibitor; epacadostat; immune microenvironment; metabolome; pancreatic cancer
    DOI:  https://doi.org/10.3389/fonc.2023.1142838
  4. Nat Commun. 2023 07 18. 14(1): 4317
    Adipose tissue and skeletal muscle wasting precede clinical diagnosis of pancreatic cancer.
    Ana Babic, Michael H Rosenthal, Tilak K Sundaresan, Natalia Khalaf, Valerie Lee, Lauren K Brais, Maureen Loftus, Leah Caplan, Sarah Denning, Anamol Gurung, Joanna Harrod, Khoschy Schawkat, Chen Yuan, Qiao-Li Wang, Alice A Lee, Leah H Biller, Matthew B Yurgelun, Kimmie Ng, Jonathan A Nowak, Andrew J Aguirre, Sangeeta N Bhatia, Matthew G Vander Heiden, Stephen K Van Den Eeden, Bette J Caan, Brian M Wolpin.
      Patients with pancreatic cancer commonly develop weight loss and muscle wasting. Whether adipose tissue and skeletal muscle losses begin before diagnosis and the potential utility of such losses for earlier cancer detection are not well understood. We quantify skeletal muscle and adipose tissue areas from computed tomography (CT) imaging obtained 2 months to 5 years before cancer diagnosis in 714 pancreatic cancer cases and 1748 matched controls. Adipose tissue loss is identified up to 6 months, and skeletal muscle wasting is identified up to 18 months before the clinical diagnosis of pancreatic cancer and is not present in the matched control population. Tissue losses are of similar magnitude in cases diagnosed with localized compared with metastatic disease and are not correlated with at-diagnosis circulating levels of CA19-9. Skeletal muscle wasting occurs in the 1-2 years before pancreatic cancer diagnosis and may signal an upcoming diagnosis of pancreatic cancer.
    DOI:  https://doi.org/10.1038/s41467-023-40024-3
  5. Nat Commun. 2023 Jul 20. 14(1): 4367
    Oncolytic viruses engineered to enforce cholesterol efflux restore tumor-associated macrophage phagocytosis and anti-tumor immunity in glioblastoma.
    Shiqun Wang, Wei Yan, Lingkai Kong, Shuguang Zuo, Jingyi Wu, Chunxiao Zhu, Huaping Huang, Bohao He, Jie Dong, Jiwu Wei.
      The codependency of cholesterol metabolism sustains the malignant progression of glioblastoma (GBM) and effective therapeutics remain scarce. In orthotopic GBM models in male mice, we identify that codependent cholesterol metabolism in tumors induces phagocytic dysfunction in monocyte-derived tumor-associated macrophages (TAMs), resulting in disease progression. Manipulating cholesterol efflux with apolipoprotein A1 (ApoA1), a cholesterol reverse transporter, restores TAM phagocytosis and reactivates TAM-T cell antitumor immunity. Cholesterol metabolomics analysis of in vivo-sorted TAMs further reveals that ApoA1 mediates lipid-related metabolic remodeling and lowers 7-ketocholesterol levels, which directly inhibits tumor necrosis factor signaling in TAMs through mitochondrial translation inhibition. An ApoA1-armed oncolytic adenovirus is also developed, which restores antitumor immunity and elicits long-term tumor-specific immune surveillance. Our findings provide insight into the mechanisms by which cholesterol metabolism impairs antitumor immunity in GBM and offer an immunometabolic approach to target cholesterol disturbances in GBM.
    DOI:  https://doi.org/10.1038/s41467-023-39683-z
  6. Am J Physiol Cell Physiol. 2023 Jul 17.
    The SLC38A5/SNAT5 amino acid transporter: from pathophysiology to pro-cancer roles in the tumor microenvironment.
    Giuseppe Taurino, Martina Chiu, Massimiliano G Bianchi, Erika Griffini, Ovidio Bussolati.
      SLC38A5/SNAT5 is a system N transporter that can mediate net inward or outward transmembrane fluxes of neutral amino acids coupled with Na+ (symport) and H+ (antiport). Its preferential substrates are amino acids with side chains containing amide (glutamine, and asparagine) or imidazole (histidine) groups, but also serine, glycine and alanine are transported by the carrier. Expressed in the pancreas, intestinal tract, brain, liver, bone marrow, and placenta, it is regulated at mRNA and protein levels by mTORC1 and WNT/β-catenin pathways, and it is sensitive to pH, nutritional stress, inflammation, and hypoxia. SNAT5 expression has been found to be altered in pathological conditions such as chronic inflammatory diseases, gestational complications, chronic metabolic acidosis and malnutrition. Growing experimental evidence shows that SNAT5 is overexpressed in several types of cancer cells. Moreover, recently published results indicate that SNAT5 expression in stromal cells can support the metabolic exchanges occurring in the tumor microenvironment of asparagine-auxotroph tumors. We review the functional role of the SNAT5 transporter in pathophysiology and propose that, due to its peculiar operational and regulatory features, SNAT5 may play important pro-cancer roles when expressed either in neoplastic or in stromal cells of glutamine-auxotroph tumors.
    Keywords:  Amino acid transport; Asparagine; Cancer; Glutamine; Metabolic diseases
    DOI:  https://doi.org/10.1152/ajpcell.00169.2023
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