bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2024–03–24
seven papers selected by
Oltea Sampetrean, Keio University
  1. Leveraging macrophage metabolism for anticancer therapy: opportunities and pitfalls.
  2. Targeting metabolism to improve CAR-T cells therapeutic efficacy.
  3. Metabolic reprogramming in the CLL TME; potential for new therapeutic targets.
  4. Co-inhibition of TGF-β and PD-L1 pathways in a metastatic colorectal cancer mouse model triggers interferon responses, innate cells and T cells, alongside metabolic changes and tumor resistance.
  5. Glutamine metabolism prognostic index predicts tumour microenvironment characteristics and therapeutic efficacy in ovarian cancer.
  6. High hypoxia status in pancreatic cancer is associated with multiple hallmarks of an immunosuppressive tumor microenvironment.
  7. Activation of GPR81 by lactate drives tumour-induced cachexia.
  1. Trends Pharmacol Sci. 2024 Mar 16. pii: S0165-6147(24)00045-2. [Epub ahead of print]
    Leveraging macrophage metabolism for anticancer therapy: opportunities and pitfalls.
    Piyal Saha, Paul Ettel, Thomas Weichhart.
      Tumor-associated macrophages (TAMs) constitute an important part of the tumor microenvironment (TME) that regulates tumor progression. Tumor-derived signals, hypoxia, and competition for nutrients influence TAMs to reprogram their cellular metabolism. This altered metabolic profile creates a symbiotic communication between tumor and other immune cells to support tumor growth. In addition, the metabolic profile of TAMs regulates the expression of immune checkpoint molecules. The dynamic plasticity also allows TAMs to reshape their metabolism in response to modern therapeutic strategies. Therefore, over the years, a significant number of approaches have been implicated to reprogram cancer-promoting metabolism in TAMs. In this review, we discuss the current strategies and pitfalls, along with upcoming promising opportunities in leveraging TAM metabolism for developing better therapeutic approaches against cancer.
    Keywords:  macrophages; metabolism; tumor
    DOI:  https://doi.org/10.1016/j.tips.2024.02.005
  2. Chin Med J (Engl). 2024 Mar 19.
    Targeting metabolism to improve CAR-T cells therapeutic efficacy.
    Shasha Liu, Yuyu Zhao, Yaoxin Gao, Feng Li, Yi Zhang.
       ABSTRACT: Chimeric antigen receptor T (CAR-T) cell therapy achieved advanced progress in the treatment of hematological tumors. However, the application of CAR-T cell therapy for solid tumors still faces many challenges. Competition with tumor cells for metabolic resources in an already nutrient-poor tumor microenvironment is a major contributing cause to CAR-T cell therapy's low effectiveness. Abnormal metabolic processes are now acknowledged to shape the tumor microenvironment, which is characterized by increased interstitial fluid pressure, low pH level, hypoxia, accumulation of immunosuppressive metabolites, and mitochondrial dysfunction. These factors are important contributors to restriction of T cell proliferation, cytokine release, and suppression of tumor cell-killing ability. This review provides an overview of how different metabolites regulate T cell activity, analyzes the current dilemmas, and proposes key strategies to reestablish the CAR-T cell therapy's effectiveness through targeting metabolism, with the aim of providing new strategies to surmount the obstacle in the way of solid tumor CAR-T cell treatment.
    DOI:  https://doi.org/10.1097/CM9.0000000000003046
  3. Semin Hematol. 2024 Feb 15. pii: S0037-1963(24)00016-7. [Epub ahead of print]
    Metabolic reprogramming in the CLL TME; potential for new therapeutic targets.
    Helga Simon-Molas, Chiara Montironi, Anna Kabanova, Eric Eldering.
      Chronic lymphocytic leukemia (CLL) cells circulate between peripheral (PB) blood and lymph node (LN) compartments, and strictly depend on microenvironmental factors for proliferation, survival and drug resistance. All cancer cells display metabolic reprogramming and CLL is no exception - though the inert status of the PB CLL cells has hampered detailed insight into these processes. We summarize previous work on reactive oxygen species (ROS), oxidative stress, and hypoxia, as well as the important roles of Myc, and PI3K/Akt/mTor pathways. In vitro co-culture systems and gene expression analyses have provided a partial picture of CLL LN metabolism. New broad omics techniques allow to obtain molecular and also single-cell level understanding of CLL plasticity and metabolic reprogramming. We summarize recent developments and describe the new concept of glutamine addiction for CLL, which may hold therapeutic promise.
    Keywords:  glutamine; metabolism; oncogenes; transporters; tumor microenvironment
    DOI:  https://doi.org/10.1053/j.seminhematol.2024.02.001
  4. Oncoimmunology. 2024 ;13(1): 2330194
    Co-inhibition of TGF-β and PD-L1 pathways in a metastatic colorectal cancer mouse model triggers interferon responses, innate cells and T cells, alongside metabolic changes and tumor resistance.
    Reshmi Nair, Tamsin R M Lannagan, Rene Jackstadt, Anna Andrusaite, John Cole, Caitlin Boyne, Robert J B Nibbs, Owen J Sansom, Simon Milling.
      Colorectal cancer (CRC) is the third most prevalent cancer worldwide with a high mortality rate (20-30%), especially due to metastasis to adjacent organs. Clinical responses to chemotherapy, radiation, targeted and immunotherapies are limited to a subset of patients making metastatic CRC (mCRC) difficult to treat. To understand the therapeutic modulation of immune response in mCRC, we have used a genetically engineered mouse model (GEMM), "KPN", which resembles the human 'CMS4'-like subtype. We show here that transforming growth factor (TGF-β1), secreted by KPN organoids, increases cancer cell proliferation, and inhibits splenocyte activation in vitro. TGF-β1 also inhibits activation of naive but not pre-activated T cells, suggesting differential effects on specific immune cells. In vivo, the inhibition of TGF-β inflames the KPN tumors, causing infiltration of T cells, monocytes and monocytic intermediates, while reducing neutrophils and epithelial cells. Co-inhibition of TGF-β and PD-L1 signaling further enhances cytotoxic CD8+T cells and upregulates innate immune response and interferon gene signatures. However, simultaneous upregulation of cancer-related metabolic genes correlated with limited control of tumor burden and/or progression despite combination treatment. Our study illustrates the importance of using GEMMs to predict better immunotherapies for mCRC.
    Keywords:  Check point inhibition; T-lymphocytes; colorectal cancer; drug-mediated resistance; immunotherapy; metabolism; mice models; myeloid cells
    DOI:  https://doi.org/10.1080/2162402X.2024.2330194
  5. J Cell Mol Med. 2024 Apr;28(7): e18198
    Glutamine metabolism prognostic index predicts tumour microenvironment characteristics and therapeutic efficacy in ovarian cancer.
    Lingling Gao, Zheng Wei, Feiquan Ying, Lin Huang, Jingni Zhang, Si Sun, Zehua Wang, Jing Cai, Yuan Zhang.
      Mounting evidence has highlighted the multifunctional characteristics of glutamine metabolism (GM) in cancer initiation, progression and therapeutic regimens. However, the overall role of GM in the tumour microenvironment (TME), clinical stratification and therapeutic efficacy in patients with ovarian cancer (OC) has not been fully elucidated. Here, three distinct GM clusters were identified and exhibited different prognostic values, biological functions and immune infiltration in TME. Subsequently, glutamine metabolism prognostic index (GMPI) was constructed as a new scoring model to quantify the GM subtypes and was verified as an independent predictor of OC. Patients with low-GMPI exhibited favourable survival outcomes, lower enrichment of several oncogenic pathways, less immunosuppressive cell infiltration and better immunotherapy responses. Single-cell sequencing analysis revealed a unique evolutionary trajectory of OC cells from high-GMPI to low-GMPI, and OC cells with different GMPI might communicate with distinct cell populations through ligand-receptor interactions. Critically, the therapeutic efficacy of several drug candidates was validated based on patient-derived organoids (PDOs). The proposed GMPI could serve as a reliable signature for predicting patient prognosis and contribute to optimising therapeutic strategies for OC.
    Keywords:  metabolism reprogramming; molecular subtype; ovarian tumour; patient-derived organoids (PDOs); single-cell RNA transcriptome
    DOI:  https://doi.org/10.1111/jcmm.18198
  6. Front Immunol. 2024 ;15 1360629
    High hypoxia status in pancreatic cancer is associated with multiple hallmarks of an immunosuppressive tumor microenvironment.
    Hassan Sadozai, Animesh Acharjee, Hateem Z Kayani, Thomas Gruber, Reginald M Gorczynski, Bernard Burke.
       Introduction: Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, is a particularly lethal disease that is often diagnosed late and is refractory to most forms of treatment. Tumour hypoxia is a key hallmark of PDAC and is purported to contribute to multiple facets of disease progression such as treatment resistance, increased invasiveness, metabolic reprogramming, and immunosuppression.
    Methods: We used the Buffa gene signature as a hypoxia score to profile transcriptomics datasets from PDAC cases. We performed cell-type deconvolution and gene expression profiling approaches to compare the immunological phenotypes of cases with low and high hypoxia scores. We further supported our findings by qPCR analyses in PDAC cell lines cultured in hypoxic conditions.
    Results: First, we demonstrated that this hypoxia score is associated with increased tumour grade and reduced survival suggesting that this score is correlated to disease progression. Subsequently, we compared the immune phenotypes of cases with high versus low hypoxia score expression (HypoxiaHI vs. HypoxiaLOW) to show that high hypoxia is associated with reduced levels of T cells, NK cells and dendritic cells (DC), including the crucial cDC1 subset. Concomitantly, immune-related gene expression profiling revealed that compared to HypoxiaLOW tumours, mRNA levels for multiple immunosuppressive molecules were notably elevated in HypoxiaHI cases. Using a Random Forest machine learning approach for variable selection, we identified LGALS3 (Galectin-3) as the top gene associated with high hypoxia status and confirmed its expression in hypoxic PDAC cell lines.
    Discussion: In summary, we demonstrated novel associations between hypoxia and multiple immunosuppressive mediators in PDAC, highlighting avenues for improving PDAC immunotherapy by targeting these immune molecules in combination with hypoxia-targeted drugs.
    Keywords:  galectins; hypoxia; immune checkpoint; pancreatic ductal adenocarcinoma (PDAC); tumor microenvironment (TME)
    DOI:  https://doi.org/10.3389/fimmu.2024.1360629
  7. Nat Metab. 2024 Mar 18.
    Activation of GPR81 by lactate drives tumour-induced cachexia.
    Xidan Liu, Shijin Li, Qionghua Cui, Bujing Guo, Wanqiu Ding, Jie Liu, Li Quan, Xiaochuan Li, Peng Xie, Li Jin, Ye Sheng, Wenxin Chen, Kai Wang, Fanxin Zeng, Yifu Qiu, Changlu Liu, Yan Zhang, Fengxiang Lv, Xinli Hu, Rui-Ping Xiao.
      Cachexia affects 50-80% of patients with cancer and accounts for 20% of cancer-related death, but the underlying mechanism driving cachexia remains elusive. Here we show that circulating lactate levels positively correlate with the degree of body weight loss in male and female patients suffering from cancer cachexia, as well as in clinically relevant mouse models. Lactate infusion per se is sufficient to trigger a cachectic phenotype in tumour-free mice in a dose-dependent manner. Furthermore, we demonstrate that adipose-specific G-protein-coupled receptor (GPR)81 ablation, similarly to global GPR81 deficiency, ameliorates lactate-induced or tumour-induced adipose and muscle wasting in male mice, revealing adipose GPR81 as the major mediator of the catabolic effects of lactate. Mechanistically, lactate/GPR81-induced cachexia occurs independently of the well-established protein kinase A catabolic pathway, but it is mediated by a signalling cascade sequentially activating Gi-Gβγ-RhoA/ROCK1-p38. These findings highlight the therapeutic potential of targeting GPR81 for the treatment of this life-threatening complication of cancer.
    DOI:  https://doi.org/10.1038/s42255-024-01011-0
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