bims-tumime Biomed News
on Tumor microenvironment and metabolism
Issue of 2024‒02‒25
seven papers selected by
Alex Muir, University of Chicago

  1. Metabolites. 2024 Feb 02. pii: 103. [Epub ahead of print]14(2):
      Solid tumors frequently present a heterogeneous tumor microenvironment. Because tumors have the potential to proliferate quickly, the consequence is a reduction in the nutrients, a reduction in the pH (<6.8), and a hypoxic environment. Although it is often assumed that tumor clones show a similar growth rate with little variations in nutrient consumption, the present study shows how growth-specific rate (µ), the specific rates of glucose, lactate, and glutamine consumption (qS), and the specific rates of lactate and glutamate production (qP) of 2D-cultured lung tumor cells are affected by changes in their environment. We determined in lung tumor cells (A427, A549, Calu-1, and SKMES-1) the above mentioned kinetic parameters during the exponential phase under different culture conditions, varying the predominant carbon source, pH, and oxygen tension. MCF-7 cells, a breast tumor cell line that can consume lactate, and non-transformed fibroblast cells (MRC-5) were included as controls. We also analyzed how cell-cycle progression and the amino acid transporter CD98 expression were affected. Our results show that: (1) In glucose presence, μ increased, but qS Glucose and qP Lactate decreased when tumor cells were cultured under acidosis as opposed to neutral conditions; (2) most lung cancer cell lines consumed lactate under normoxia or hypoxia; (3) although qS Glutamine diminished under hypoxia or acidosis, it slightly increased in lactate presence, a finding that was associated with CD98 upregulation; and (4) under acidosis, G0/G1 arrest was induced in A427 cancer cells, although this phenomenon was significantly increased when glucose was changed by lactate as the predominant carbon-source. Hence, our results provide an understanding of metabolic responses that tumor cells develop to survive under stressful conditions, providing clues for developing promising opportunities to improve traditional cancer therapies.
    Keywords:  glucose deprivation; hypoxia; lactic acidosis; specific growth rate; tumor metabolism; tumor microenvironment
  2. Trends Endocrinol Metab. 2024 Feb 20. pii: S1043-2760(24)00023-7. [Epub ahead of print]
      Methionine restriction (MR) has been shown to suppress tumor growth and improve the responses to various anticancer therapies. However, methionine itself is required for the proliferation, activation, and differentiation of T cells that are crucial for antitumor immunity. The dual impact of methionine, that influences both tumor and immune cells, has generated concerns regarding the potential consequences of MR on T cell immunity and its possible role in promoting cancer. In this review we systemically examine current literature on the interactions between dietary methionine, cancer cells, and immune cells. Based on recent findings on MR in immunocompetent animals, we further discuss how tumor stage-specific methionine dependence of immune cells and cancer cells in the tumor microenvironment could ultimately dictate the response of tumors to MR.
    Keywords:  antitumor immunity; gut microbiota; methylation; redox homeostasis; sulfur metabolism
  3. Trends Cancer. 2024 Feb 21. pii: S2405-8033(23)00242-X. [Epub ahead of print]
      Tumor-resident microbes (TRM) are an integral component of the tumor microenvironment (TME). TRM can influence tumor growth, distant dissemination, and response to therapies by interfering with molecular pathways in tumor cells as well as with other components of the TME. Novel technologies are improving the identification and visualization of cell type-specific microbes in the TME. The mechanisms that mediate the role of TRM at the primary tumors and metastatic sites are being elucidated. This knowledge is providing novel perspectives for targeting microbes or using microbial interventions for cancer interception or therapy.
    Keywords:  cancer; immunity; metastasis; microenvironment; tumor-resident microbes; tumorigenesis
  4. Trends Immunol. 2024 Feb 22. pii: S1471-4906(24)00026-7. [Epub ahead of print]
      The heterogeneity and plasticity of neutrophils in tumor-host interactions and how tumor signals induce reprogramming of neutrophil subpopulations need further investigation. Ng et al. recently reported that a hypoxic-glycolytic niche in mouse tumors could reprogram mature and immature neutrophils into a long-lived and terminally-differentiated subset, which promoted angiogenesis and tumor growth.
    Keywords:  long-lived neutrophil subpopulation; reprogramming; tumor hypoxic and glycolytic niche; tumor-associated neutrophils
  5. Annu Rev Immunol. 2024 Feb 21.
      Immune checkpoint blockade (ICB) induces a remarkable and durable response in a subset of cancer patients. However, most patients exhibit either primary or acquired resistance to ICB. This resistance arises from a complex interplay of diverse dynamic mechanisms within the tumor microenvironment (TME). These mechanisms include genetic, epigenetic, and metabolic alterations that prevent T cell trafficking to the tumor site, induce immune cell dysfunction, interfere with antigen presentation, drive heightened expression of coinhibitory molecules, and promote tumor survival after immune attack. The TME worsens ICB resistance through the formation of immunosuppressive networks via immune inhibition, regulatory metabolites, and abnormal resource consumption. Finally, patient lifestyle factors, including obesity and microbiome composition, influence ICB resistance. Understanding the heterogeneity of cellular, molecular, and environmental factors contributing to ICB resistance is crucial to develop targeted therapeutic interventions that enhance the clinical response. This comprehensive overview highlights key mechanisms of ICB resistance that may be clinically translatable. Expected final online publication date for the Annual Review of Immunology, Volume 42 is April 2024. Please see for revised estimates.
  6. Cell Rep Med. 2024 Feb 10. pii: S2666-3791(24)00052-1. [Epub ahead of print] 101429
      Obesity is a risk factor for colorectal cancer (CRC), and the involvement of gut microbiota in the pathogenesis of obesity and CRC is widely recognized. However, the landscape of fecal microbiome and metabolome distinguishing patients with obesity-related CRC from obesity remains unknown. Here, we utilize metagenomic sequencing and metabolomics from 522 patients with CRC and healthy controls to identify the characteristics of obese CRC. Our integrated analysis reveals that obesity-related CRC is characterized by elevated Peptostreptococcus stomatis, dysregulated fatty acids and phospholipids, and altered Kyoto Encyclopedia of Genes and Genomes pathways involving glycerophospholipid metabolism and lipopolysaccharide synthesis. Correlation analysis unveils microbial interactions in obesity, where the probiotic Faecalibacterium prausnitzii and the tumor-promoting species P. stomatis may engage in cross-feeding, thereby promoting tumorigenesis. In vitro experiments affirm enhanced growth under cross-feeding conditions. The mutualistic microbe-microbe interaction may contribute to the association between obesity and elevated CRC risk. Additionally, diagnostic models incorporating BMI-specific microbial biomarkers display promise for precise CRC screening.
    Keywords:  colorectal cancer; cross-feeding; gut microbiota; lipid metabolism; metabolome; metagenome; obesity; short-chain fatty acid
  7. Theranostics. 2024 ;14(4): 1683-1700
      Background: Pancreatic ductal adenocarcinoma (PDAC) is an insidious, rapidly progressing malignancy of the gastrointestinal tract. Due to its dense fibrous stroma and complex tumor microenvironment, neither of which is sensitive to radiotherapy, pancreatic adenocarcinoma is one of the malignancies with the poorest prognosis. Therefore, detailed elucidation of the inhibitory microenvironment of PDAC is essential for the development of novel therapeutic strategies. Methods: We analyzed the association between cancer-associated fibroblasts (CAFs) and resistance to ferroptosis in PDAC using conditioned CAF medium and co-culture of pancreatic cancer cells. Abnormal cysteine metabolism was observed in CAFs using non-targeted metabolomics analysis with liquid chromatography-tandem mass spectrometry (LC-MS/MS). The regulatory effects of cysteine were investigated in PDAC cells through measurement of cell cloning, cell death, cell function, and EdU assays. The effects of exogenous cysteine intake were examined in a mouse xenograft model and the effects of the cysteine pathway on ferroptosis in PDAC were investigated by western blotting, measurement of glutathione and reactive oxygen species levels, among others. Results: It was found that CAFs played a critical role in PDAC metabolism by secreting cysteine, which could increase tumor resistance to ferroptosis. A previously unrecognized function of the sulfur transfer pathway in CAFs was identified, which increased the extracellular supply of cysteine to support glutathione synthesis and thus inducing ferroptosis resistance. Cysteine secretion by CAFs was found to be mediated by the TGF-β/SMAD3/ATF4 signaling axis. Conclusion: Taken together, the findings demonstrate a novel metabolic relationship between CAFs and cancer cells, in which cysteine generated by CAFs acts as a substrate in the prevention of oxidative damage in PDAC and thus suggests new therapeutic targets for PDAC.
    Keywords:  CAF; TME; cysteine; metabolism; pancreatic cancer