bims-mecami 2023-10-15 papers

bims-mecami

Biomed News

on Metabolic interactions between cancer cells and their microenvironment

Issue of 2023–10–15
eight papers selected by
Oltea Sampetrean, Keio University

The yin and yang of itaconate metabolism and its impact on the tumor microenvironment.
Glycolysis-cholesterol metabolic axis in immuno-oncology microenvironment: emerging role in immune cells and immunosuppressive signaling.
Systematic investigation of mitochondrial transfer between cancer cells and T cells at single-cell resolution.
Arginine reprograms metabolism in liver cancer via RBM39.
Pancreatic Cancer-Secreted Proteins: Targeting Their Functions in Tumor Microenvironment.
Editorial: Epigenetic, metabolic, and transcriptional regulation of immune cell plasticity and functions in cancer and non-cancer diseases.
Metabolic interventions to enhance immunotherapy and targeted therapy efficacy in advanced colorectal cancer.
Cancer-associated fibroblasts impair the cytotoxic function of NK cells in gastric cancer by inducing ferroptosis via iron regulation.

Curr Opin Biotechnol. 2023 Oct 06. pii: S0958-1669(23)00106-4. [Epub ahead of print]84 102996

The yin and yang of itaconate metabolism and its impact on the tumor microenvironment.

Fangfang Chen, Birte Dowerg, Thekla Cordes.

The tumor microenvironment (TME) consists of a network of metabolically interconnected tumor and immune cell types. Macrophages influence the metabolic composition within the TME, which directly impacts the metabolic state and drug response of tumors. The accumulation of oncometabolites, such as succinate, fumarate, and 2-hydroxyglutarate, represents metabolic vulnerabilities in cancer that can be targeted therapeutically. Immunometabolites are emerging as metabolic regulators of the TME impacting immune cell functions and cancer cell growth. Here, we discuss recent discoveries on the potential impact of itaconate on the TME. We highlight how itaconate influences metabolic pathways relevant to immune responses and cancer cell proliferation. We also consider the therapeutic implications of manipulating itaconate metabolism as an immunotherapeutic strategy to constrain tumor growth.

DOI: https://doi.org/10.1016/j.copbio.2023.102996
Cell Biosci. 2023 Oct 13. 13(1): 189

Glycolysis-cholesterol metabolic axis in immuno-oncology microenvironment: emerging role in immune cells and immunosuppressive signaling.

Jing Jin, Qijie Zhao, Zhigong Wei, Keliang Chen, Yonglin Su, Xiaolin Hu, Xingchen Peng.

  Cell proliferation and function require nutrients, energy, and biosynthesis activity to duplicate repertoires for each daughter. It is therefore not surprising that tumor microenvironment (TME) metabolic reprogramming primarily orchestrates the interaction between tumor and immune cells. Tumor metabolic reprogramming affords bioenergetic, signaling intermediates, and biosynthesis requirements for both malignant and immune cells. Different immune cell subsets are recruited into the TME, and these manifestations have distinct effects on tumor progression and therapeutic outcomes, especially the mutual contribution of glycolysis and cholesterol metabolism. In particularly, glycolysis-cholesterol metabolic axis interconnection plays a critical role in the TME modulation, and their changes in tumor metabolism appear to be a double-edged sword in regulating various immune cell responses and immunotherapy efficacy. Hence, we discussed the signature manifestation of the glycolysis-cholesterol metabolic axis and its pivotal role in tumor immune regulation. We also highlight how hypothetical combinations of immunotherapy and glycolysis/cholesterol-related metabolic interventions unleash the potential of anti-tumor immunotherapies, as well as developing more effective personalized treatment strategies.

Keywords:  Glycolysis-Cholesterol Metabolic Axis; Immune Cells; Immunosuppressive; Tumor microenvironment (TME)

DOI:  https://doi.org/10.1186/s13578-023-01138-9
Cancer Cell. 2023 Oct 09. pii: S1535-6108(23)00319-7. [Epub ahead of print]41(10): 1788-1802.e10

Systematic investigation of mitochondrial transfer between cancer cells and T cells at single-cell resolution.

Hongyi Zhang, Xuexin Yu, Jianfeng Ye, Huiyu Li, Jing Hu, Yuhao Tan, Yan Fang, Esra Akbay, Fulong Yu, Chen Weng, Vijay G Sankaran, Robert M Bachoo, Elizabeth Maher, John Minna, Anli Zhang, Bo Li.

  Mitochondria (MT) participate in most metabolic activities of mammalian cells. A near-unidirectional mitochondrial transfer from T cells to cancer cells was recently observed to "metabolically empower" cancer cells while "depleting immune cells," providing new insights into tumor-T cell interaction and immune evasion. Here, we leverage single-cell RNA-seq technology and introduce MERCI, a statistical deconvolution method for tracing and quantifying mitochondrial trafficking between cancer and T cells. Through rigorous benchmarking and validation, MERCI accurately predicts the recipient cells and their relative mitochondrial compositions. Application of MERCI to human cancer samples identifies a reproducible MT transfer phenotype, with its signature genes involved in cytoskeleton remodeling, energy production, and TNF-α signaling pathways. Moreover, MT transfer is associated with increased cell cycle activity and poor clinical outcome across different cancer types. In summary, MERCI enables systematic investigation of an understudied aspect of tumor-T cell interactions that may lead to the development of therapeutic opportunities.

Keywords:  Mitochondrial Transfer; Statistical Deconvolution; T cell dysfunction; Tumor-Immune Interaction; mtDNA sequencing.; single cell genomics

DOI:  https://doi.org/10.1016/j.ccell.2023.09.003
Cell. 2023 Sep 26. pii: S0092-8674(23)01032-2. [Epub ahead of print]

Arginine reprograms metabolism in liver cancer via RBM39.

Dirk Mossmann, Christoph Müller, Sujin Park, Brendan Ryback, Marco Colombi, Nathalie Ritter, Diana Weißenberger, Eva Dazert, Mairene Coto-Llerena, Sandro Nuciforo, Lauriane Blukacz, Caner Ercan, Veronica Jimenez, Salvatore Piscuoglio, Fatima Bosch, Luigi M Terracciano, Uwe Sauer, Markus H Heim, Michael N Hall.

  Metabolic reprogramming is a hallmark of cancer. However, mechanisms underlying metabolic reprogramming and how altered metabolism in turn enhances tumorigenicity are poorly understood. Here, we report that arginine levels are elevated in murine and patient hepatocellular carcinoma (HCC), despite reduced expression of arginine synthesis genes. Tumor cells accumulate high levels of arginine due to increased uptake and reduced arginine-to-polyamine conversion. Importantly, the high levels of arginine promote tumor formation via further metabolic reprogramming, including changes in glucose, amino acid, nucleotide, and fatty acid metabolism. Mechanistically, arginine binds RNA-binding motif protein 39 (RBM39) to control expression of metabolic genes. RBM39-mediated upregulation of asparagine synthesis leads to enhanced arginine uptake, creating a positive feedback loop to sustain high arginine levels and oncogenic metabolism. Thus, arginine is a second messenger-like molecule that reprograms metabolism to promote tumor growth.

Keywords:  AGMAT; ARG1; ASNS; RBM39; arginine; hepatocellular carcinoma; indisulam; metabolism

DOI:  https://doi.org/10.1016/j.cell.2023.09.011
Cancers (Basel). 2023 Oct 01. pii: 4825. [Epub ahead of print]15(19):

Pancreatic Cancer-Secreted Proteins: Targeting Their Functions in Tumor Microenvironment.

Anna Lisa Cammarota, Antonia Falco, Anna Basile, Carlo Molino, Massimiliano Chetta, Gianni D'Angelo, Liberato Marzullo, Margot De Marco, Maria Caterina Turco, Alessandra Rosati.

  Pancreatic Ductal Adenocarcinoma (PDAC) is a ravaging disease with a poor prognosis, requiring a more detailed understanding of its biology to foster the development of effective therapies. The unsatisfactory results of treatments targeting cell proliferation and its related mechanisms suggest a shift in focus towards the inflammatory tumor microenvironment (TME). Here, we discuss the role of cancer-secreted proteins in the complex TME tumor-stroma crosstalk, shedding lights on druggable molecular targets for the development of innovative, safer and more efficient therapeutic strategies.

Keywords:  cell signaling; monoclonal antibodies; pancreatic ductal adenocarcinoma; secretome; small molecules; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers15194825
Front Immunol. 2023 ;14 1284124

Editorial: Epigenetic, metabolic, and transcriptional regulation of immune cell plasticity and functions in cancer and non-cancer diseases.

Yun Dai, Dong Ren, Yafeng He, Huanfa Yi.



Keywords:  cancer; epigenetic remodeling; immune cells; non-cancer disease; transcriptional reprogramming

DOI:  https://doi.org/10.3389/fimmu.2023.1284124
Curr Opin Chem Biol. 2023 Oct 06. pii: S1367-5931(23)00139-4. [Epub ahead of print]77 102401

Metabolic interventions to enhance immunotherapy and targeted therapy efficacy in advanced colorectal cancer.

Helena Oliveres, Marta Cascante, Joan Maurel.

  Current standard-of-care for metastatic colorectal cancer patients includes chemotherapy and anti-angiogenic or anti-epidermal growth factor receptor for microsatellite stable tumors and pembrolizumab for microsatellite instable tumors. However, despite the available therapies, the prognosis remains poor. In recent years, new drugs combined with immune checkpoint inhibitors have been tested in microsatellite stable metastatic colorectal cancer patients, but the benefit was modest. Here, we review the metabolic interactions between the immune microenvironment and cancer cells. More specifically, we highlight potential correlatives of tumor immune and metabolic features with transcriptomic classifications such as the Consensus Molecular Subtype. Finally, we discuss the unmet need of immune-metabolic signatures and the value of a new signature (IMMETCOLS) for guiding new strategies in metastatic colorectal cancer. We conclude that the field is ready to propose customized strategies for modifying metabolism and improving immunotherapy and targeted therapy efficacy.

Keywords:  Immunotherapy; Metabolism; Resistance

DOI:  https://doi.org/10.1016/j.cbpa.2023.102401
Redox Biol. 2023 Oct 06. pii: S2213-2317(23)00324-5. [Epub ahead of print]67 102923

Cancer-associated fibroblasts impair the cytotoxic function of NK cells in gastric cancer by inducing ferroptosis via iron regulation.

Lizhong Yao, Junyi Hou, Xiongyan Wu, Yifan Lu, Zhijian Jin, Zhenjia Yu, Beiqin Yu, Jianfang Li, Zhongyin Yang, Chen Li, Min Yan, Zhenggang Zhu, Bingya Liu, Chao Yan, Liping Su.

  As the predominant immunosuppressive component within the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) inhibit Natural Killer cell (NK cell) activity to promote tumor progression and immune escape; however, the mechanisms of cross-talk between CAFs and NK cells in gastric cancer (GC) remain poorly understood. In this study, we demonstrate that NK cell levels are inversely correlated with CAFs abundance in human GC. CAFs impair the anti-tumor capacity of NK cells by inducing ferroptosis, a cell death process characterized by the accumulation of iron-dependent lipid peroxides. CAFs induce ferroptosis in NK cells by promoting iron overload; conversely, decreased intracellular iron levels protect NK cells against CAF-induced ferroptosis. Mechanistically, CAFs increase the labile iron pool within NK cells via iron export into the TME, which is mediated by the upregulated expression of iron regulatory genes ferroportin1 and hephaestin in CAFs. Moreover, CAF-derived follistatin like protein 1(FSTL1) upregulates NCOA4 expression in NK cells via the DIP2A-P38 pathway, and NCOA4-mediated ferritinophagy is required for CAF-induced NK cell ferroptosis. In a human patient-derived organoid model, functional targeting of CAFs using a combination of deferoxamine and FSTL1-neutralizing antibody significantly alleviate CAF-induced NK cell ferroptosis and boost the cytotoxicity of NK cells against GC. This study demonstrates a novel mechanism of suppression of NK cell activity by CAFs in the TME and presents a potential therapeutic approach to augment the immune response against GC mediated by NK cells.

Keywords:  Cancer-associated fibroblasts; Ferritinophagy; Ferroptosis; Iron regulation; NK cells

DOI:  https://doi.org/10.1016/j.redox.2023.102923