bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2024–03–31
ten papers selected by
Oltea Sampetrean, Keio University
  1. Targeting the Warburg Effect in Cancer: Where Do We Stand?
  2. The Noncanonical Functions of Metabolites in Tumor Progression.
  3. Editorial overview: Tumor-stroma crosstalk: Shaping and characterizing the metabolic microenvironment of tumors.
  4. ATF4-SLC7A11-GSH axis mediates the acquisition of immunosuppressive properties by activated CD4+ T cells in low arginine condition.
  5. Tumor-secreted FGF21 acts as an immune suppressor by rewiring cholesterol metabolism of CD8+T cells.
  6. Pericyte signaling via soluble guanylate cyclase shapes the vascular niche and microenvironment of tumors.
  7. Glutamine antagonist DRP-104 suppresses tumor growth and enhances response to checkpoint blockade in KEAP1 mutant lung cancer.
  8. Glioblastoma stem cell metabolism and immunity.
  9. The emerging role of lactate in tumor microenvironment and its clinical relevance.
  10. A lactate metabolism-related signature predicting patient prognosis and immune microenvironment in ovarian cancer.
  1. Int J Mol Sci. 2024 Mar 08. pii: 3142. [Epub ahead of print]25(6):
    Targeting the Warburg Effect in Cancer: Where Do We Stand?
    Ignasi Barba, Laura Carrillo-Bosch, Joan Seoane.
      The Warburg effect, characterized by the preferential conversion of glucose to lactate even in the presence of oxygen and functional mitochondria, is a prominent metabolic hallmark of cancer cells and has emerged as a promising therapeutic target for cancer therapy. Elevated lactate levels and acidic pH within the tumor microenvironment (TME) resulting from glycolytic profoundly impact various cellular populations, including macrophage reprogramming and impairment of T-cell functionality. Altogether, the Warburg effect has been shown to promote tumor progression and immunosuppression through multiple mechanisms. This review provides an overview of the current understanding of the Warburg effect in cancer and its implications. We summarize recent pharmacological strategies aimed at targeting glycolytic enzymes, highlighting the challenges encountered in achieving therapeutic efficacy. Additionally, we examine the utility of the Warburg effect as an early diagnostic tool. Finally, we discuss the multifaceted roles of lactate within the TME, emphasizing its potential as a therapeutic target to disrupt metabolic interactions between tumor and immune cells, thereby enhancing anti-tumor immunity.
    Keywords:  Warburg effect; aerobic glycolysis; immunomodulation; tumor metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms25063142
  2. Metabolites. 2024 Mar 19. pii: 171. [Epub ahead of print]14(3):
    The Noncanonical Functions of Metabolites in Tumor Progression.
    Siyang Wu, Yijun Qi, Weiwei Yang.
      Metabolic reprogramming has emerged as a prominent hallmark of cancer, characterized by substantial alterations in nutrient uptake and intracellular metabolic pathways. Consequently, intracellular metabolite concentrations undergo significant changes which can contribute to tumorigenesis through diverse mechanisms. Beyond their classical roles in regulating metabolic pathway flux, metabolites exhibit noncanonical functions that play a crucial role in tumor progression. In this review, we delve into the nonclassical functions of metabolites in the context of tumor progression, with a particular focus on their capacity to modulate gene expression and cell signaling. Furthermore, we discuss the potential exploitation of these nonclassical functions in the enhancement of cancer therapy.
    Keywords:  metabolic reprogramming; metabolites; noncanonical functions of metabolites; tumor progressions
    DOI:  https://doi.org/10.3390/metabo14030171
  3. Curr Opin Biotechnol. 2024 Mar 22. pii: S0958-1669(24)00031-4. [Epub ahead of print]87 103095
    Editorial overview: Tumor-stroma crosstalk: Shaping and characterizing the metabolic microenvironment of tumors.
    Seth Parker, Thekla Cordes.
      
    DOI:  https://doi.org/10.1016/j.copbio.2024.103095
  4. Cell Rep. 2024 Mar 23. pii: S2211-1247(24)00323-1. [Epub ahead of print]43(4): 113995
    ATF4-SLC7A11-GSH axis mediates the acquisition of immunosuppressive properties by activated CD4+ T cells in low arginine condition.
    Ziqi Zou, Qian Cheng, Jiajie Zhou, Chenyao Guo, Andreas V Hadjinicolaou, Mariolina Salio, Xinghua Liang, Cuiyu Yang, Yue Du, Weiran Yao, Dongrui Wang, Vincenzo Cerundolo, Qingqing Wang, Meng Xia.
      The tumor microenvironment (TME) is restricted in metabolic nutrients including the semi-essential amino acid arginine. While complete arginine deprivation causes T cell dysfunction, it remains unclear how arginine levels fluctuate in the TME to shape T cell fates. Here, we find that the 20-μM low arginine condition, representing the levels found in the plasma of patients with cancers, confers Treg-like immunosuppressive capacities upon activated T cells. In vivo mouse tumor models and human single-cell RNA-sequencing datasets reveal positive correlations between low arginine condition and intratumoral Treg accumulation. Mechanistically, low arginine-activated T cells engage in metabolic and transcriptional reprogramming, using the ATF4-SLC7A11-GSH axis, to preserve their suppressive function. These findings improve our understanding of the role of arginine in human T cell biology with potential applications for immunotherapy strategies.
    Keywords:  CP: Immunology; SLC7A11; T cells; arginine; immunosuppression; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2024.113995
  5. Cell Metab. 2024 Mar 26. pii: S1550-4131(24)00092-5. [Epub ahead of print]
    Tumor-secreted FGF21 acts as an immune suppressor by rewiring cholesterol metabolism of CD8+T cells.
    Cegui Hu, Wen Qiao, Xiang Li, Zhi-Kun Ning, Jiang Liu, Sumiya Dalangood, Hanjun Li, Xiang Yu, Zhen Zong, Zhenke Wen, Jun Gui.
      
    DOI:  https://doi.org/10.1016/j.cmet.2024.03.013
  6. EMBO J. 2024 Mar 25.
    Pericyte signaling via soluble guanylate cyclase shapes the vascular niche and microenvironment of tumors.
    Jing Zhu, Wu Yang, Jianyun Ma, Hao He, Zhen Liu, Xiaolan Zhu, Xueyang He, Jing He, Zhan Chen, Xiaoliang Jin, Xiaohong Wang, Kaiwen He, Wu Wei, Junhao Hu.
      Pericytes and endothelial cells (ECs) constitute the fundamental components of blood vessels. While the role of ECs in tumor angiogenesis and the tumor microenvironment is well appreciated, pericyte function in tumors remains underexplored. In this study, we used pericyte-specific deletion of the nitric oxide (NO) receptor, soluble guanylate cyclase (sGC), to investigate via single-cell RNA sequencing how pericytes influence the vascular niche and the tumor microenvironment. Our findings demonstrate that pericyte sGC deletion disrupts EC-pericyte interactions, impairing Notch-mediated intercellular communication and triggering extensive transcriptomic reprogramming in both pericytes and ECs. These changes further extended their influence to neighboring cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) through paracrine signaling, collectively suppressing tumor growth. Inhibition of pericyte sGC has minimal impact on quiescent vessels but significantly increases the vulnerability of angiogenic tumor vessels to conventional anti-angiogenic therapy. In conclusion, our findings elucidate the role of pericytes in shaping the tumor vascular niche and tumor microenvironment and support pericyte sGC targeting as a promising strategy for improving anti-angiogenic therapy for cancer treatment.
    Keywords:  Pericyte; Soluble Guanylate Cyclase; Tumor Microenvironment; Vascular Niche
    DOI:  https://doi.org/10.1038/s44318-024-00078-5
  7. Sci Adv. 2024 Mar 29. 10(13): eadm9859
    Glutamine antagonist DRP-104 suppresses tumor growth and enhances response to checkpoint blockade in KEAP1 mutant lung cancer.
    Ray Pillai, Sarah E LeBoeuf, Yuan Hao, Connie New, Jenna L E Blum, Ali Rashidfarrokhi, Shih Ming Huang, Christian Bahamon, Warren L Wu, Burcu Karadal-Ferrena, Alberto Herrera, Ellie Ivanova, Michael Cross, Jozef P Bossowski, Hongyu Ding, Makiko Hayashi, Sahith Rajalingam, Triantafyllia Karakousi, Volkan I Sayin, Kamal M Khanna, Kwok-Kin Wong, Robert Wild, Aristotelis Tsirigos, John T Poirier, Charles M Rudin, Shawn M Davidson, Sergei B Koralov, Thales Papagiannakopoulos.
      Loss-of-function mutations in KEAP1 frequently occur in lung cancer and are associated with poor prognosis and resistance to standard of care treatment, highlighting the need for the development of targeted therapies. We previously showed that KEAP1 mutant tumors consume glutamine to support the metabolic rewiring associated with NRF2-dependent antioxidant production. Here, using preclinical patient-derived xenograft models and antigenic orthotopic lung cancer models, we show that the glutamine antagonist prodrug DRP-104 impairs the growth of KEAP1 mutant tumors. We find that DRP-104 suppresses KEAP1 mutant tumors by inhibiting glutamine-dependent nucleotide synthesis and promoting antitumor T cell responses. Using multimodal single-cell sequencing and ex vivo functional assays, we demonstrate that DRP-104 reverses T cell exhaustion, decreases Tregs, and enhances the function of CD4 and CD8 T cells, culminating in an improved response to anti-PD1 therapy. Our preclinical findings provide compelling evidence that DRP-104, currently in clinical trials, offers a promising therapeutic approach for treating patients with KEAP1 mutant lung cancer.
    DOI:  https://doi.org/10.1126/sciadv.adm9859
  8. Cancer Metastasis Rev. 2024 Mar 26.
    Glioblastoma stem cell metabolism and immunity.
    Joseph Hawly, Micaela G Murcar, Alejandro Schcolnik-Cabrera, Mark E Issa.
      Despite enormous efforts being invested in the development of novel therapies for brain malignancies, there remains a dire need for effective treatments, particularly for pediatric glioblastomas. Their poor prognosis has been attributed to the fact that conventional therapies target tumoral cells, but not glioblastoma stem cells (GSCs). GSCs are characterized by self-renewal, tumorigenicity, poor differentiation, and resistance to therapy. These characteristics represent the fundamental tools needed to recapitulate the tumor and result in a relapse. The mechanisms by which GSCs alter metabolic cues and escape elimination by immune cells are discussed in this article, along with potential strategies to harness effector immune cells against GSCs. As cellular immunotherapy is making significant advances in a variety of cancers, leveraging this underexplored reservoir may result in significant improvements in the treatment options for brain malignancies.
    Keywords:  Brain tumors; Cancer metabolism; Cancer stem cells; Elimination; Equilibrium; Escape; Immunoediting; Immunotherapy; Microglia; Natural killer cells; Resistance; Self-renewal; Surveillance; T cells; Tumorigenicity
    DOI:  https://doi.org/10.1007/s10555-024-10183-w
  9. Cancer Lett. 2024 Mar 26. pii: S0304-3835(24)00230-1. [Epub ahead of print] 216837
    The emerging role of lactate in tumor microenvironment and its clinical relevance.
    Sihan Chen, Yining Xu, Wei Zhuo, Lu Zhang.
      In recent years, the significant impact of lactate in the tumor microenvironment has been greatly documented. Acting not only as an energy substance in tumor metabolism, lactate is also an imperative signaling molecule. It plays key roles in metabolic remodeling, protein lactylation, immunosuppression, drug resistance, epigenetics and tumor metastasis, which has a tight relation with cancer patients' poor prognosis. This review illustrates the roles lactate plays in different aspects of tumor progression and drug resistance. From the comprehensive effects that lactate has on tumor metabolism and tumor immunity, the therapeutic targets related to it are expected to bring new hope for cancer therapy.
    Keywords:  Drug resistance; Lactic acid; Lactylation; Metabolic symbiosis; Tumor progression
    DOI:  https://doi.org/10.1016/j.canlet.2024.216837
  10. Front Endocrinol (Lausanne). 2024 ;15 1372413
    A lactate metabolism-related signature predicting patient prognosis and immune microenvironment in ovarian cancer.
    Linhua Zhu, Zhuoqun Lin, Kai Wang, Jiaxin Gu, Xiaojing Chen, Ruizhe Chen, Lingfang Wang, Xiaodong Cheng.
       Introduction: Ovarian cancer (OV) is a highly lethal gynecological malignancy with a poor prognosis. Lactate metabolism is crucial for tumor cell survival, proliferation, and immune evasion. Our study aims to investigate the role of lactate metabolism-related genes (LMRGs) in OV and their potential as biomarkers for prognosis, immune microenvironment, and immunotherapy response.
    Methods: Ovarian samples were collected from the TCGA cohort. And 12 lactate-related pathways were identified from the MsigDB database. Differentially expressed genes within these pathways were designated as LMRGs, which undergo unsupervised clustering to identify distinct clusters based on LMRGs. Subsequently, we assessed survival outcomes, immune cell infiltration levels, Hallmaker pathway activation patterns, and chemotaxis among different subtypes. After conducting additional unsupervised clustering based on differentially expressed genes (DEGs), significant differences in the expression of LMRGs between the two clusters were observed. The differentially expressed genes were subjected to subsequent functional enrichment analysis. Furthermore, we construct a model incorporating LMRGs. Subsequently, the lactate score for each tumor sample was calculated based on this model, facilitating the classification of samples into high and low groups according to their respective lactate scores. Distinct groups examined disparities in survival prognosis, copy number variation (CNV), single nucleotide variation (SNV), and immune infiltration. The lactate score served as a quantitative measure of OV's lactate metabolism pattern and an independent prognostic factor.
    Results: This study investigated the potential role of LMRGs in tumor microenvironment diversity and prognosis in OV, suggesting that LMRGs play a crucial role in OV progression and the tumor microenvironment, thus serving as novel indicators for prognosis, immune microenvironment status, and response to immunotherapy.
    Keywords:  immune microenvironment; lactate; metabolism; ovarian cancer; prognostic signature
    DOI:  https://doi.org/10.3389/fendo.2024.1372413
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