bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2023‒07‒02
nine papers selected by
Oltea Sampetrean, Keio University
  1. Beggars banquet: Metabolism in the tumor immune microenvironment and cancer therapy.
  2. Shutting off the fuel supply to target metabolic vulnerabilities in multiple myeloma.
  3. The Metabolism and Immune Environment in Diffuse Large B-Cell Lymphoma.
  4. Mitochondrial transfer from cancer associated fibroblasts increases migration in aggressive breast cancer.
  5. Ferroptosis of immune cells in the tumor microenvironment.
  6. Fatty Acid Metabolites and the Tumor Microenvironment as Potent Regulators of Cancer Stem Cell Signaling.
  7. Mitochondria Transfer from Mesenchymal Stem Cells Confers Chemoresistance to Glioblastoma Stem Cells through Metabolic Rewiring.
  8. Increased glucose availability sensitizes pancreatic cancer to chemotherapy.
  9. Characterization of the metabolic alteration-modulated tumor microenvironment mediated by TP53 mutation and hypoxia.
  1. Cell Metab. 2023 Jun 20. pii: S1550-4131(23)00213-9. [Epub ahead of print]
    Beggars banquet: Metabolism in the tumor immune microenvironment and cancer therapy.
    Weiping Zou, Douglas R Green.
      Metabolic programming in the tumor microenvironment (TME) alters tumor immunity and immunotherapeutic response in tumor-bearing mice and patients with cancer. Here, we review immune-related functions of core metabolic pathways, key metabolites, and crucial nutrient transporters in the TME, discuss their metabolic, signaling, and epigenetic impact on tumor immunity and immunotherapy, and explore how these insights can be applied to the development of more effective modalities to potentiate the function of T cells and sensitize tumor cell receptivity to immune attack, thereby overcoming therapeutic resistance.
    Keywords:  T cell; checkpoint; immunotherapy; metabolism; metabolite; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cmet.2023.06.003
  2. Front Oncol. 2023 ;13 1141851
    Shutting off the fuel supply to target metabolic vulnerabilities in multiple myeloma.
    Priyanka S Rana, Krishna Goparaju, James J Driscoll.
      Pathways that govern cellular bioenergetics are deregulated in tumor cells and represent a hallmark of cancer. Tumor cells have the capacity to reprogram pathways that control nutrient acquisition, anabolism and catabolism to enhance their growth and survival. Tumorigenesis requires the autonomous reprogramming of key metabolic pathways that obtain, generate and produce metabolites from a nutrient-deprived tumor microenvironment to meet the increased bioenergetic demands of cancer cells. Intra- and extracellular factors also have a profound effect on gene expression to drive metabolic pathway reprogramming in not only cancer cells but also surrounding cell types that contribute to anti-tumor immunity. Despite a vast amount of genetic and histologic heterogeneity within and between cancer types, a finite set of pathways are commonly deregulated to support anabolism, catabolism and redox balance. Multiple myeloma (MM) is the second most common hematologic malignancy in adults and remains incurable in the vast majority of patients. Genetic events and the hypoxic bone marrow milieu deregulate glycolysis, glutaminolysis and fatty acid synthesis in MM cells to promote their proliferation, survival, metastasis, drug resistance and evasion of immunosurveillance. Here, we discuss mechanisms that disrupt metabolic pathways in MM cells to support the development of therapeutic resistance and thwart the effects of anti-myeloma immunity. A better understanding of the events that reprogram metabolism in myeloma and immune cells may reveal unforeseen vulnerabilities and advance the rational design of drug cocktails that improve patient survival.
    Keywords:  fatty acid synthesis; glycolysis; metabolism; multiple myeloma; oxidative phosphorylation; proteasome inhibitor
    DOI:  https://doi.org/10.3389/fonc.2023.1141851
  3. Metabolites. 2023 Jun 08. pii: 734. [Epub ahead of print]13(6):
    The Metabolism and Immune Environment in Diffuse Large B-Cell Lymphoma.
    Jianbo Wu, Fuqing Meng, Danyang Ran, Yalong Song, Yunkun Dang, Fan Lai, Longyan Yang, Mi Deng, Yuqin Song, Jun Zhu.
      Cells utilize different metabolic processes to maintain their growth and differentiation. Tumor cells have made some metabolic changes to protect themselves from malnutrition. These metabolic alterations affect the tumor microenvironment and macroenvironment. Developing drugs targeting these metabolic alterations could be a good direction. In this review, we briefly introduce metabolic changes/regulations of the tumor macroenvironment and microenvironment and summarize potential drugs targeting the metabolism in diffuse large B-cell lymphoma.
    Keywords:  diffuse large B-cell lymphoma; immune environment; metabolic alteration; metabolic regulation; therapeutic strategy
    DOI:  https://doi.org/10.3390/metabo13060734
  4. J Cell Sci. 2023 Jun 26. pii: jcs.260419. [Epub ahead of print]
    Mitochondrial transfer from cancer associated fibroblasts increases migration in aggressive breast cancer.
    Kayla F Goliwas, Sarah Libring, Emily Berestesky, Shayan Gholizadeh, Samantha C Schwager, Andra R Frost, Thomas R Gaborski, Jian Zhang, Cynthia A Reinhart-King.
      Cancer associated fibroblasts (CAFs) have distinct roles within the tumor microenvironment, which may impact the mode and efficacy of tumor cell migration. CAFs are known to increase invasion of less-aggressive breast cancer cells through matrix remodeling and leader-follower dynamics. Here, we demonstrate that CAFs communicate with breast cancer cells through the formation of contact-dependent tunneling nanotubes (TNTs) that allow for the exchange of cargo between cell types. The transferring of CAF mitochondria is an integral cargo component, and CAF mitochondria are sufficient to increase the 3D migration of cancer cells. This cargo transfer results in an increase in mitochondrial ATP production in cancer cells while having negligible impact on glycolytic ATP production. Manually increasing mitochondrial oxidative phosphorylation (OXPHOS) by providing extra substrates for OXPHOS fails to enhance cancer cell migration unless glycolysis is maintained at a constant level. Together, these data indicate that tumor-stromal crosstalk via TNTs and the associated metabolic symbiosis is a finely controlled mechanism by which tumor cells co-opt their microenvironment to promote cancer progression and may become a potential therapeutic target.
    Keywords:  ATP production.; Bioenergetics; CAF; Reverse Warburg effect; Tumor microenvironment; Tumor spheroid; Tunneling nanotube
    DOI:  https://doi.org/10.1242/jcs.260419
  5. Trends Pharmacol Sci. 2023 Jun 26. pii: S0165-6147(23)00132-3. [Epub ahead of print]
    Ferroptosis of immune cells in the tumor microenvironment.
    Rina Kim, Devon Taylor, Robert H Vonderheide, Dmitry I Gabrilovich.
      Ferroptosis is a distinct form of cell death driven by the accumulation of peroxidized lipids. Characterized by alterations in redox lipid metabolism, ferroptosis has been implicated in a variety of cellular processes, including cancer. Induction of ferroptosis is considered a novel way to kill tumor cells, especially cells resistant to radiation and chemotherapy. However, in recent years, a new paradigm has emerged. In addition to promoting tumor cell death, ferroptosis causes potent immune suppression in the tumor microenvironment (TME) by affecting both innate and adaptive immune responses. In this review, we discuss the dual role of ferroptosis in the antitumor and protumorigenic functions of immune cells in cancer. We suggest strategies for targeting ferroptosis, taking onto account its ambiguous role in cancer.
    Keywords:  MDSC; cancer; ferroptosis; macrophages; monocytes; neutrophils
    DOI:  https://doi.org/10.1016/j.tips.2023.06.005
  6. Metabolites. 2023 May 31. pii: 709. [Epub ahead of print]13(6):
    Fatty Acid Metabolites and the Tumor Microenvironment as Potent Regulators of Cancer Stem Cell Signaling.
    Toshiyuki Murai, Satoru Matsuda.
      Individual cancer cells are not equal but are organized into a cellular hierarchy in which only a rare few leukemia cells can self-renew in a manner reminiscent of the characteristic stem cell properties. The PI3K/AKT pathway functions in a variety of cancers and plays a critical role in the survival and proliferation of healthy cells under physiologic conditions. In addition, cancer stem cells might exhibit a variety of metabolic reprogramming phenotypes that cannot be completely attributed to the intrinsic heterogeneity of cancer. Given the heterogeneity of cancer stem cells, new strategies with single-cell resolution will become a powerful tool to eradicate the aggressive cell population harboring cancer stem cell phenotypes. Here, this article will provide an overview of the most important signaling pathways of cancer stem cells regarding their relevance to the tumor microenvironment and fatty acid metabolism, suggesting valuable strategies among cancer immunotherapies to inhibit the recurrence of tumors.
    Keywords:  PI3K/AKT; cancer stem cells; epithelial to mesenchymal transition; lipid metabolites; metabolic reprogramming; phosphoinositide 3-kinase; tumor microenvironment
    DOI:  https://doi.org/10.3390/metabo13060709
  7. Cancer Res Commun. 2023 Jun;3(6): 1041-1056
    Mitochondria Transfer from Mesenchymal Stem Cells Confers Chemoresistance to Glioblastoma Stem Cells through Metabolic Rewiring.
    Jean Nakhle, Khattar Khattar, Tülin Özkan, Adel Boughlita, Daouda Abba Moussa, Amélie Darlix, Frédérique Lorcy, Valérie Rigau, Luc Bauchet, Sabine Gerbal-Chaloin, Martine Daujat-Chavanieu, Floriant Bellvert, Laurent Turchi, Thierry Virolle, Jean-Philippe Hugnot, Nicolas Buisine, Mireille Galloni, Valérie Dardalhon, Anne-Marie Rodriguez, Marie-Luce Vignais.
      Glioblastomas (GBM) are heterogeneous tumors with high metabolic plasticity. Their poor prognosis is linked to the presence of glioblastoma stem cells (GSC), which support resistance to therapy, notably to temozolomide (TMZ). Mesenchymal stem cells (MSC) recruitment to GBM contributes to GSC chemoresistance, by mechanisms still poorly understood. Here, we provide evidence that MSCs transfer mitochondria to GSCs through tunneling nanotubes, which enhances GSCs resistance to TMZ. More precisely, our metabolomics analyses reveal that MSC mitochondria induce GSCs metabolic reprograming, with a nutrient shift from glucose to glutamine, a rewiring of the tricarboxylic acid cycle from glutaminolysis to reductive carboxylation and increase in orotate turnover as well as in pyrimidine and purine synthesis. Metabolomics analysis of GBM patient tissues at relapse after TMZ treatment documents increased concentrations of AMP, CMP, GMP, and UMP nucleotides and thus corroborate our in vitro analyses. Finally, we provide a mechanism whereby mitochondrial transfer from MSCs to GSCs contributes to GBM resistance to TMZ therapy, by demonstrating that inhibition of orotate production by Brequinar (BRQ) restores TMZ sensitivity in GSCs with acquired mitochondria. Altogether, these results identify a mechanism for GBM resistance to TMZ and reveal a metabolic dependency of chemoresistant GBM following the acquisition of exogenous mitochondria, which opens therapeutic perspectives based on synthetic lethality between TMZ and BRQ.Significance: Mitochondria acquired from MSCs enhance the chemoresistance of GBMs. The discovery that they also generate metabolic vulnerability in GSCs paves the way for novel therapeutic approaches.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-23-0144
  8. Nat Commun. 2023 Jun 28. 14(1): 3823
    Increased glucose availability sensitizes pancreatic cancer to chemotherapy.
    Ali Vaziri-Gohar, Jonathan J Hue, Ata Abbas, Hallie J Graor, Omid Hajihassani, Mehrdad Zarei, George Titomihelakis, John Feczko, Moeez Rathore, Sylwia Chelstowska, Alexander W Loftus, Rui Wang, Mahsa Zarei, Maryam Goudarzi, Renliang Zhang, Belinda Willard, Li Zhang, Adam Kresak, Joseph E Willis, Gi-Ming Wang, Curtis Tatsuoka, Joseph M Salvino, Ilya Bederman, Henri Brunengraber, Costas A Lyssiotis, Jonathan R Brody, Jordan M Winter.
      Pancreatic Ductal Adenocarcinoma (PDAC) is highly resistant to chemotherapy. Effective alternative therapies have yet to emerge, as chemotherapy remains the best available systemic treatment. However, the discovery of safe and available adjuncts to enhance chemotherapeutic efficacy can still improve survival outcomes. We show that a hyperglycemic state substantially enhances the efficacy of conventional single- and multi-agent chemotherapy regimens against PDAC. Molecular analyses of tumors exposed to high glucose levels reveal that the expression of GCLC (glutamate-cysteine ligase catalytic subunit), a key component of glutathione biosynthesis, is diminished, which in turn augments oxidative anti-tumor damage by chemotherapy. Inhibition of GCLC phenocopies the suppressive effect of forced hyperglycemia in mouse models of PDAC, while rescuing this pathway mitigates anti-tumor effects observed with chemotherapy and high glucose.
    DOI:  https://doi.org/10.1038/s41467-023-38921-8
  9. Comput Biol Med. 2023 May 29. pii: S0010-4825(23)00543-7. [Epub ahead of print]163 107078
    Characterization of the metabolic alteration-modulated tumor microenvironment mediated by TP53 mutation and hypoxia.
    Kunpeng Luo, Zhipeng Qian, Yanan Jiang, Dongxu Lv, Kaibin Zhu, Jing Shao, Ying Hu, Chengqian Lv, Qianqian Huang, Yang Gao, Shizhu Jin, Desi Shang.
      BACKGROUND: TP53 mutation and hypoxia play an essential role in cancer progression. However, the metabolic reprogramming and tumor microenvironment (TME) heterogeneity mediated by them are still not fully understood.METHODS: The multi-omics data of 32 cancer types and immunotherapy cohorts were acquired to comprehensively characterize the metabolic reprogramming pattern and the TME across cancer types and explore immunotherapy candidates. An assessment model for metabolic reprogramming was established by integration of multiple machine learning methods, including lasso regression, neural network, elastic network, and survival support vector machine (SVM). Pharmacogenomics analysis and in vitro assay were conducted to identify potential therapeutic drugs.
    RESULTS: First, we identified metabolic subtype A (hypoxia-TP53 mutation subtype) and metabolic subtype B (non-hypoxia-TP53 wildtype subtype) in hepatocellular carcinoma (HCC) and showed that metabolic subtype A had an "immune inflamed" microenvironment. Next, we established an assessment model for metabolic reprogramming, which was more effective compared to the traditional prognostic indicators. Then, we identified a potential targeting drug, teniposide. Finally, we performed the pan-cancer analysis to illustrate the role of metabolic reprogramming in cancer and found that the metabolic alteration (MA) score was positively correlated with tumor mutational burden (TMB), neoantigen load, and homologous recombination deficiency (HRD) across cancer types. Meanwhile, we demonstrated that metabolic reprogramming mediated a potential immunotherapy-sensitive microenvironment in bladder cancer and validated it in an immunotherapy cohort.
    CONCLUSION: Metabolic alteration mediated by hypoxia and TP53 mutation is associated with TME modulation and tumor progression across cancer types. In this study, we analyzed the role of metabolic alteration in cancer and propose a predictive model for cancer prognosis and immunotherapy responsiveness. We also explored a potential therapeutic drug, teniposide.
    Keywords:  Hypoxia; Metabolic alteration; Precise oncology; TP53 mutation; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.compbiomed.2023.107078
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