bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2024–04–28
ten papers selected by
Oltea Sampetrean, Keio University
  1. The Tumor Microenvironment: Signal Transduction.
  2. Cancer cell metabolism and antitumour immunity.
  3. Extracellular domains of CARs reprogramme T cell metabolism without antigen stimulation.
  4. Editorial: Extracellular vesicles as means of the activation, metabolic change induction, and remodeling of the tumor microenvironment.
  5. A glycolytic metabolite that drives BRCA2 haploinsufficiency.
  6. Lipid metabolism in tumor-infiltrating regulatory T cells: perspective to precision immunotherapy.
  7. Single-cell analysis revealing the metabolic landscape of prostate cancer.
  8. Metabolomics-driven discovery of therapeutic targets for cancer cachexia.
  9. A dietary commensal microbe enhances antitumor immunity by activating tumor macrophages to sequester iron.
  10. Pan-cancer analysis implicates novel insights of lactate metabolism into immunotherapy response prediction and survival prognostication.
  1. Biomolecules. 2024 Apr 04. pii: 438. [Epub ahead of print]14(4):
    The Tumor Microenvironment: Signal Transduction.
    Xianhong Zhang, Haijun Ma, Yue Gao, Yabing Liang, Yitian Du, Shuailin Hao, Ting Ni.
      In the challenging tumor microenvironment (TME), tumors coexist with diverse stromal cell types. During tumor progression and metastasis, a reciprocal interaction occurs between cancer cells and their environment. These interactions involve ongoing and evolving paracrine and proximal signaling. Intrinsic signal transduction in tumors drives processes such as malignant transformation, epithelial-mesenchymal transition, immune evasion, and tumor cell metastasis. In addition, cancer cells embedded in the tumor microenvironment undergo metabolic reprogramming. Their metabolites, serving as signaling molecules, engage in metabolic communication with diverse matrix components. These metabolites act as direct regulators of carcinogenic pathways, thereby activating signaling cascades that contribute to cancer progression. Hence, gaining insights into the intrinsic signal transduction of tumors and the signaling communication between tumor cells and various matrix components within the tumor microenvironment may reveal novel therapeutic targets. In this review, we initially examine the development of the tumor microenvironment. Subsequently, we delineate the oncogenic signaling pathways within tumor cells and elucidate the reciprocal communication between these pathways and the tumor microenvironment. Finally, we give an overview of the effect of signal transduction within the tumor microenvironment on tumor metabolism and tumor immunity.
    Keywords:  signaling pathways; tumor immunity; tumor metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3390/biom14040438
  2. Nat Rev Immunol. 2024 Apr 22.
    Cancer cell metabolism and antitumour immunity.
    Mara De Martino, Jeffrey C Rathmell, Lorenzo Galluzzi, Claire Vanpouille-Box.
      Accumulating evidence suggests that metabolic rewiring in malignant cells supports tumour progression not only by providing cancer cells with increased proliferative potential and an improved ability to adapt to adverse microenvironmental conditions but also by favouring the evasion of natural and therapy-driven antitumour immune responses. Here, we review cancer cell-intrinsic and cancer cell-extrinsic mechanisms through which alterations of metabolism in malignant cells interfere with innate and adaptive immune functions in support of accelerated disease progression. Further, we discuss the potential of targeting such alterations to enhance anticancer immunity for therapeutic purposes.
    DOI:  https://doi.org/10.1038/s41577-024-01026-4
  3. Nat Metab. 2024 Apr 24.
    Extracellular domains of CARs reprogramme T cell metabolism without antigen stimulation.
    Aliya Lakhani, Ximin Chen, Laurence C Chen, Mihe Hong, Mobina Khericha, Yu Chen, Yvonne Y Chen, Junyoung O Park.
      Metabolism is an indispensable part of T cell proliferation, activation and exhaustion, yet the metabolism of chimeric antigen receptor (CAR)-T cells remains incompletely understood. CARs are composed of extracellular domains-often single-chain variable fragments (scFvs)-that determine ligand specificity and intracellular domains that trigger signalling following antigen binding. Here, we show that CARs differing only in the scFv variously reprogramme T cell metabolism. Even without exposure to antigens, some CARs increase proliferation and nutrient uptake in T cells. Using stable isotope tracers and mass spectrometry, we observed basal metabolic fluxes through glycolysis doubling and amino acid uptake overtaking anaplerosis in CAR-T cells harbouring a rituximab scFv, unlike other similar anti-CD20 scFvs. Disparate rituximab and 14G2a-based anti-GD2 CAR-T cells are similarly hypermetabolic and channel excess nutrients to nitrogen overflow metabolism. Modest overflow metabolism of CAR-T cells and metabolic compatibility between cancer cells and CAR-T cells are identified as features of efficacious CAR-T cell therapy.
    DOI:  https://doi.org/10.1038/s42255-024-01034-7
  4. Front Oncol. 2024 ;14 1407949
    Editorial: Extracellular vesicles as means of the activation, metabolic change induction, and remodeling of the tumor microenvironment.
    Michela Pozzobon, Alfredo Cappariello.
      
    Keywords:  cancer progression; clinical outlooks; extracellular vesicles; tumor microenvironment; tumor niche remodeling
    DOI:  https://doi.org/10.3389/fonc.2024.1407949
  5. Cell. 2024 Apr 25. pii: S0092-8674(24)00319-2. [Epub ahead of print]187(9): 2124-2126
    A glycolytic metabolite that drives BRCA2 haploinsufficiency.
    Peng Jiang.
      Many types of tumor cells alter metabolic pathways to meet their energy and biosynthetic demands for proliferation or stress adaptation. In this issue of Cell, Kong et al. find that the glycolytic metabolite methylglyoxal causes cancer-associated mutant single-base substitution features by inducing BRCA2 proteolysis, leading to functional haploinsufficiency of BRCA2.
    DOI:  https://doi.org/10.1016/j.cell.2024.03.028
  6. Biomark Res. 2024 Apr 22. 12(1): 41
    Lipid metabolism in tumor-infiltrating regulatory T cells: perspective to precision immunotherapy.
    Yukai Shan, Tianao Xie, Yuchao Sun, Ziyi Lu, Win Topatana, Sarun Juengpanich, Tianen Chen, Yina Han, Jiasheng Cao, Jiahao Hu, Shijie Li, Xiujun Cai, Mingyu Chen.
      Regulatory T cells (Tregs) are essential to the negative regulation of the immune system, as they avoid excessive inflammation and mediate tumor development. The abundance of Tregs in tumor tissues suggests that Tregs may be eliminated or functionally inhibited to stimulate antitumor immunity. However, immunotherapy targeting Tregs has been severely hampered by autoimmune diseases due to the systemic elimination of Tregs. Recently, emerging studies have shown that metabolic regulation can specifically target tumor-infiltrating immune cells, and lipid accumulation in TME is associated with immunosuppression. Nevertheless, how Tregs actively regulate metabolic reprogramming to outcompete effector T cells (Teffs), and how lipid metabolic reprogramming contributes to the immunomodulatory capacity of Tregs have not been fully discussed. This review will discuss the physiological processes by which lipid accumulation confers a metabolic advantage to tumor-infiltrating Tregs (TI-Tregs) and amplifies their immunosuppressive functions. Furthermore, we will provide a summary of the driving effects of various metabolic regulators on the metabolic reprogramming of Tregs. Finally, we propose that targeting the lipid metabolism of TI-Tregs could be efficacious either alone or in conjunction with immune checkpoint therapy.
    Keywords:  Immunosuppression; Lipid metabolism; Metabolic competition; Metabolic regulatory switches; Tregs; Tumor therapies
    DOI:  https://doi.org/10.1186/s40364-024-00588-8
  7. Asian J Androl. 2024 Apr 23.
    Single-cell analysis revealing the metabolic landscape of prostate cancer.
    Jing Wang, He-Kang Ding, Han-Jiang Xu, De-Kai Hu, William Hankey, Li Chen, Jun Xiao, Chao-Zhao Liang, Bing Zhao, Ling-Fan Xu.
      Tumor metabolic reprogramming is a hallmark of cancer development, and targeting metabolic vulnerabilities has been proven to be an effective approach for castration-resistant prostate cancer (CRPC) treatment. Nevertheless, treatment failure inevitably occurs, largely due to cellular heterogeneity, which cannot be deciphered by traditional bulk sequencing techniques. By employing computational pipelines for single-cell RNA sequencing, we demonstrated that epithelial cells within the prostate are more metabolically active and plastic than stromal cells. Moreover, we identified that neuroendocrine (NE) cells tend to have high metabolic rates, which might explain the high demand for nutrients and energy exhibited by neuroendocrine prostate cancer (NEPC), one of the most lethal variants of prostate cancer (PCa). Additionally, we demonstrated through computational and experimental approaches that variation in mitochondrial activity is the greatest contributor to metabolic heterogeneity among both tumor cells and nontumor cells. These results establish a detailed metabolic landscape of PCa, highlight a potential mechanism of disease progression, and emphasize the importance of future studies on tumor heterogeneity and the tumor microenvironment from a metabolic perspective.
    DOI:  https://doi.org/10.4103/aja20243
  8. J Cachexia Sarcopenia Muscle. 2024 Apr 21.
    Metabolomics-driven discovery of therapeutic targets for cancer cachexia.
    Pengfei Cui, Xiaoyi Li, Caihua Huang, Donghai Lin.
      Cancer cachexia (CC) is a devastating metabolic syndrome characterized by skeletal muscle wasting and body weight loss, posing a significant burden on the health and survival of cancer patients. Despite ongoing efforts, effective treatments for CC are still lacking. Metabolomics, an advanced omics technique, offers a comprehensive analysis of small-molecule metabolites involved in cellular metabolism. In CC research, metabolomics has emerged as a valuable tool for identifying diagnostic biomarkers, unravelling molecular mechanisms and discovering potential therapeutic targets. A comprehensive search strategy was implemented to retrieve relevant articles from primary databases, including Web of Science, Google Scholar, Scopus and PubMed, for CC and metabolomics. Recent advancements in metabolomics have deepened our understanding of CC by uncovering key metabolic signatures and elucidating underlying mechanisms. By targeting crucial metabolic pathways including glucose metabolism, amino acid metabolism, fatty acid metabolism, bile acid metabolism, ketone body metabolism, steroid metabolism and mitochondrial energy metabolism, it becomes possible to restore metabolic balance and alleviate CC symptoms. This review provides a comprehensive summary of metabolomics studies in CC, focusing on the discovery of potential therapeutic targets and the evaluation of modulating specific metabolic pathways for CC treatment. By harnessing the insights derived from metabolomics, novel interventions for CC can be developed, leading to improved patient outcomes and enhanced quality of life.
    Keywords:  Cancer cachexia; Metabolic pathway; Metabolomics; Therapeutic target
    DOI:  https://doi.org/10.1002/jcsm.13465
  9. Nat Immunol. 2024 Apr 25.
    A dietary commensal microbe enhances antitumor immunity by activating tumor macrophages to sequester iron.
    Garima Sharma, Amit Sharma, Inhae Kim, Dong Gon Cha, Somi Kim, Eun Seo Park, Jae Gyun Noh, Juhee Lee, Ja Hyeon Ku, Yoon Ha Choi, JungHo Kong, Haena Lee, Haeun Ko, Juhun Lee, Anna Notaro, Seol Hee Hong, Joon Haeng Rhee, Sang Geon Kim, Cristina De Castro, Antonio Molinaro, Kunyoo Shin, Sanguk Kim, Jong Kyoung Kim, Dipayan Rudra, Sin-Hyeog Im.
      Innate immune cells generate a multifaceted antitumor immune response, including the conservation of essential nutrients such as iron. These cells can be modulated by commensal bacteria; however, identifying and understanding how this occurs is a challenge. Here we show that the food commensal Lactiplantibacillus plantarum IMB19 augments antitumor immunity in syngeneic and xenograft mouse tumor models. Its capsular heteropolysaccharide is the major effector molecule, functioning as a ligand for TLR2. In a two-pronged manner, it skews tumor-associated macrophages to a classically active phenotype, leading to generation of a sustained CD8+ T cell response, and triggers macrophage 'nutritional immunity' to deploy the high-affinity iron transporter lipocalin-2 for capturing and sequestering iron in the tumor microenvironment. This process induces a cycle of tumor cell death, epitope expansion and subsequent tumor clearance. Together these data indicate that food commensals might be identified and developed into 'oncobiotics' for a multi-layered approach to cancer therapy.
    DOI:  https://doi.org/10.1038/s41590-024-01816-x
  10. J Exp Clin Cancer Res. 2024 Apr 25. 43(1): 125
    Pan-cancer analysis implicates novel insights of lactate metabolism into immunotherapy response prediction and survival prognostication.
    Dongjie Chen, Pengyi Liu, Xiongxiong Lu, Jingfeng Li, Debin Qi, Longjun Zang, Jiayu Lin, Yihao Liu, Shuyu Zhai, Da Fu, Yuanchi Weng, Hongzhe Li, Baiyong Shen.
       BACKGROUND: Immunotherapy has emerged as a potent clinical approach for cancer treatment, but only subsets of cancer patients can benefit from it. Targeting lactate metabolism (LM) in tumor cells as a method to potentiate anti-tumor immune responses represents a promising therapeutic strategy.
    METHODS: Public single-cell RNA-Seq (scRNA-seq) cohorts collected from patients who received immunotherapy were systematically gathered and scrutinized to delineate the association between LM and the immunotherapy response. A novel LM-related signature (LM.SIG) was formulated through an extensive examination of 40 pan-cancer scRNA-seq cohorts. Then, multiple machine learning (ML) algorithms were employed to validate the capacity of LM.SIG for immunotherapy response prediction and survival prognostication based on 8 immunotherapy transcriptomic cohorts and 30 The Cancer Genome Atlas (TCGA) pan-cancer datasets. Moreover, potential targets for immunotherapy were identified based on 17 CRISPR datasets and validated via in vivo and in vitro experiments.
    RESULTS: The assessment of LM was confirmed to possess a substantial relationship with immunotherapy resistance in 2 immunotherapy scRNA-seq cohorts. Based on large-scale pan-cancer data, there exists a notably adverse correlation between LM.SIG and anti-tumor immunity as well as imbalance infiltration of immune cells, whereas a positive association was observed between LM.SIG and pro-tumorigenic signaling. Utilizing this signature, the ML model predicted immunotherapy response and prognosis with an AUC of 0.73/0.80 in validation sets and 0.70/0.87 in testing sets respectively. Notably, LM.SIG exhibited superior predictive performance across various cancers compared to published signatures. Subsequently, CRISPR screening identified LDHA as a pan-cancer biomarker for estimating immunotherapy response and survival probability which was further validated using immunohistochemistry (IHC) and spatial transcriptomics (ST) datasets. Furthermore, experiments demonstrated that LDHA deficiency in pancreatic cancer elevated the CD8+ T cell antitumor immunity and improved macrophage antitumoral polarization, which in turn enhanced the efficacy of immunotherapy.
    CONCLUSIONS: We unveiled the tight correlation between LM and resistance to immunotherapy and further established the pan-cancer LM.SIG, holds the potential to emerge as a competitive instrument for the selection of patients suitable for immunotherapy.
    Keywords:  Immunotherapy; Lactate metabolism; Pan-cancer analysis; Survival prognostication; scRNA-seq
    DOI:  https://doi.org/10.1186/s13046-024-03042-7
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