bims-mecami 2023-08-27 papers

Issue of 2023–08–27
five papers selected by
Oltea Sampetrean, Keio University

Front Oncol. 2023 ;13 1264740

Editorial: Proteomic and metabolic reprogramming in myeloma cells within the tumor microenvironment.

Enrico Milan, Annamaria Gullà.

Keywords: IMiDs; bone marrow; metabolism; microenvironment; mitochondria; multiple myeloma; proteasome inhibitors (PI)

DOI: https://doi.org/10.3389/fonc.2023.1264740

Curr Opin Cell Biol. 2023 Aug 17. pii: S0955-0674(23)00067-4. [Epub ahead of print]84 102218

Dynamic links between mechanical forces and metabolism shape the tumor milieu.

Rebecca Bertolio, Francesco Napoletano, Giannino Del Sal.

Cell function relies on the spatiotemporal dynamics of metabolic reactions. In all physiopathological processes of tissues, mechanical forces impact the structure and function of membranes, enzymes, organelles and regulators of metabolic gene programs, thus regulating cell metabolism. In turn, metabolic pathways feedback impacts the physical properties of cell and tissues. Hence, metabolism and tissue mechanics are dynamically intertwined and continuously interact. Cancer is akin to an ecosystem, comprising tumor cells and various subpopulations of stromal cells embedded in an altered extracellular matrix. The progression of cancer, from initiation to advanced stage and metastasis, is driven by genetic mutations and crucially influenced by physical and metabolic alterations in the tumor microenvironment. These alterations also play a pivotal role in cancer cells evasion from immune surveillance and in developing resistance to treatments. Here, we highlight emerging evidence showing that mechano-metabolic circuits in cancer and stromal cells regulate multiple processes crucial for tumor progression and discuss potential approaches to improve therapeutic treatments by interfering with these circuits.

DOI: https://doi.org/10.1016/j.ceb.2023.102218

Cancer Cell Int. 2023 Aug 24. 23(1): 177

Spatially resolved visualization of reprogrammed metabolism in hepatocellular carcinoma by mass spectrometry imaging.

Bangzhen Ma, Yang Zhang, Jiwei Ma, Xinguo Chen, Chenglong Sun, Chengkun Qin.

BACKGROUND: Metabolic reprogramming refers to tumor-associated metabolic alterations during tumorigenesis and has been regarded as one of the most important features of cancer. Profiling the altered metabolites and lipids in hepatocellular carcinoma with spatial signature will not only enhance our understanding of tumor metabolic reprogramming, but also offer potential metabolic liabilities that might be exploited for hepatocellular carcinoma therapy.
METHODS: We perform matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) analysis on both hepatocellular carcinoma xenograft mouse model and hepatocellular carcinoma patients. Discriminatory metabolites that altered during the development of hepatocellular carcinoma are screened and imaged in xenograft mouse model and are further validated in 21 hepatocellular carcinoma patients.
RESULTS: We discover stepwise metabolic alterations and progressively increasing metabolic heterogeneity during the growth of hepatocellular carcinoma. Arginine and its metabolites spermine and spermidine, choline and phosphatidylcholine metabolism, and fatty acids were found to be significantly reprogrammed in hepatocellular carcinoma tissues.
CONCLUSIONS: The spatially resolved profiling of the metabolites and lipids in highly heterogeneous hepatocellular carcinoma tissue will contribute to obtaining precise metabolic information for the understanding of tumor metabolic reprogramming.

Keywords: Hepatocellular carcinoma, MALDI-MS; Metabolites, lipids; Spatially resolved imaging

DOI: https://doi.org/10.1186/s12935-023-03027-0

Cancer Res. 2023 Aug 23. pii: CAN-23-0025. [Epub ahead of print]

Matrix stiffness triggers lipid metabolic crosstalk between tumor and stromal cells to mediate bevacizumab resistance in colorectal cancer liver metastases.

Yannan Zheng, Rui Zhou, Jianan Cai, Nanyan Yang, Zhaowei Wen, Zhihua Zhang, Huiying Sun, Genjie Huang, Yijin Guan, Na Huang, Min Shi, Yulin Liao, Jianping Bin, Wangjun Liao.

Bevacizumab is an anti-vascular endothelial growth factor (VEGF) monoclonal antibody that plays an important role in the combination treatment of advanced colorectal cancer (CRC). However, resistance remains a major hurdle limiting bevacizumab efficacy, highlighting the importance of identifying mechanism of anti-angiogenic therapy resistance. Here, we investigated biophysical properties of the extracellular matrix (ECM) related to metabolic processes and acquired resistance to bevacizumab. Evaluation of paired pre- and post-treatment samples of liver metastases from 20 CRC patients treated with combination bevacizumab therapy, including 10 responders and 10 non-responders, indicated that ECM deposition in liver metastases and a highly activated fatty acid oxidation (FAO) pathway were elevated in non-responders after anti-angiogenic therapy compared to responders. In mouse models of liver metastatic CRC, anti-VEGF increased ECM deposition and FAO in CRC cells, and treatment with the FAO inhibitor etomoxir enhanced the efficacy of antiangiogenic therapy. Hepatic stellate cells (HSCs) were essential for matrix stiffness-mediated FAO in colon cancer cells. Matrix stiffness activated lipolysis in HSCs via the focal adhesion kinase (FAK)/yes-associated protein (YAP) pathway, and free fatty acids secreted by HSCs were absorbed as metabolic substrates and activated FAO in colon cancer cells. Suppressing HSC lipolysis using FAK and YAP inhibition enhanced the efficacy of anti-VEGF therapy. Together, these results indicate that bevacizumab-induced ECM remodeling triggers lipid metabolic crosstalk between colon cancer cells and HSCs. This metabolic mechanism of bevacizumab resistance mediated by the physical tumor microenvironment represents a potential therapeutic target for reversing drug resistance.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-0025

Nat Metab. 2023 Aug 21.

Glutarate regulates T cell metabolism and anti-tumour immunity.

Eleanor Minogue, Pedro P Cunha, Brennan J Wadsworth, Guinevere L Grice, Shiv K Sah-Teli, Rob Hughes, David Bargiela, Alessandro Quaranta, Javier Zurita, Robin Antrobus, Pedro Velica, Laura Barbieri, Craig E Wheelock, Peppi Koivunen, James A Nathan, Iosifina P Foskolou, Randall S Johnson.

T cell function and fate can be influenced by several metabolites: in some cases, acting through enzymatic inhibition of α-ketoglutarate-dependent dioxygenases, in others, through post-translational modification of lysines in important targets. We show here that glutarate, a product of amino acid catabolism, has the capacity to do both, and has potent effects on T cell function and differentiation. We found that glutarate exerts those effects both through α-ketoglutarate-dependent dioxygenase inhibition, and through direct regulation of T cell metabolism via glutarylation of the pyruvate dehydrogenase E2 subunit. Administration of diethyl glutarate, a cell-permeable form of glutarate, alters CD8+ T cell differentiation and increases cytotoxicity against target cells. In vivo administration of the compound is correlated with increased levels of both peripheral and intratumoural cytotoxic CD8+ T cells. These results demonstrate that glutarate is an important regulator of T cell metabolism and differentiation with a potential role in the improvement of T cell immunotherapy.

DOI: https://doi.org/10.1038/s42255-023-00855-2