bims-mecami 2023-08-20 papers

Issue of 2023‒08‒20
five papers selected by
Oltea Sampetrean, Keio University

Nat Commun. 2023 Aug 12. 14(1): 4883

Characterizing cancer metabolism from bulk and single-cell RNA-seq data using METAFlux.

Yuefan Huang, Vakul Mohanty, Merve Dede, Kyle Tsai, May Daher, Li Li, Katayoun Rezvani, Ken Chen.

Cells often alter metabolic strategies under nutrient-deprived conditions to support their survival and growth. Characterizing metabolic reprogramming in the tumor microenvironment (TME) is of emerging importance in cancer research and patient care. However, recent technologies only measure a subset of metabolites and cannot provide in situ measurements. Computational methods such as flux balance analysis (FBA) have been developed to estimate metabolic flux from bulk RNA-seq data and can potentially be extended to single-cell RNA-seq (scRNA-seq) data. However, it is unclear how reliable current methods are, particularly in TME characterization. Here, we present a computational framework METAFlux (METAbolic Flux balance analysis) to infer metabolic fluxes from bulk or single-cell transcriptomic data. Large-scale experiments using cell-lines, the cancer genome atlas (TCGA), and scRNA-seq data obtained from diverse cancer and immunotherapeutic contexts, including CAR-NK cell therapy, have validated METAFlux's capability to characterize metabolic heterogeneity and metabolic interaction amongst cell types.

DOI: https://doi.org/10.1038/s41467-023-40457-w

Oncoimmunology. 2023 ;12(1): 2244330

L-Kynurenine participates in cancer immune evasion by downregulating hypoxic signaling in T lymphocytes.

Stephanie Schlichtner, Inna M Yasinska, Elena Klenova, Maryam Abooali, Gurprit S Lall, Steffen M Berger, Sabrina Ruggiero, Dietmar Cholewa, Milan Milošević, Bernhard F Gibbs, Elizaveta Fasler-Kan, Vadim V Sumbayev.

Malignant tumors often escape anticancer immune surveillance by suppressing the cytotoxic functions of T lymphocytes. While many of these immune evasion networks include checkpoint proteins, small molecular weight compounds, such as the amino acid L-kynurenine (LKU), could also substantially contribute to the suppression of anti-cancer immunity. However, the biochemical mechanisms underlying the suppressive effects of LKU on T-cells remain unclear. Here, we report for the first time that LKU suppresses T cell function as an aryl hydrocarbon receptor (AhR) ligand. The presence of LKU in T cells is associated with AhR activation, which results in competition between AhR and hypoxia-inducible factor 1 alpha (HIF-1α) for the AhR nuclear translocator, ARNT, leading to T cell exhaustion. The expression of indoleamine 2,3-dioxygenase 1 (IDO1, the enzyme that leads to LKU generation) is induced by the TGF-β-Smad-3 pathway. We also show that IDO-negative cancers utilize an alternative route for LKU production via the endogenous inflammatory mediator, the high mobility group box 1 (HMGB-1)-interferon-gamma (IFN-γ) axis. In addition, other IDO-negative tumors (like T-cell lymphomas) trigger IDO1 activation in eosinophils present in the tumor microenvironment (TME). These mechanisms suppress cytotoxic T cell function, and thus support the tumor immune evasion machinery.

Keywords: T cells; cancer; immune checkpoints; immune escape; kynurenine

DOI: https://doi.org/10.1080/2162402X.2023.2244330

Carcinogenesis. 2023 Aug 16. pii: bgad058. [Epub ahead of print]

On the road to colorectal cancer development: crosstalk between the gut microbiota, metabolic reprogramming and epigenetic modifications.

Anqi Chen, Zhengting Jiang, Lingli Cai, Dong Tang.

An increasing number of studies have reported the role of gut microbes in colorectal cancer (CRC) development, as they can be influenced by dietary metabolism and mediate alterations in host epigenetics, ultimately affecting CRC. Intake of specific dietary components can affect gut microbial composition and function, and their metabolism regulates important epigenetic functions that may influence CRC risk. Gut microbes can regulate epigenetic modifications through nutrient metabolism, including histone modification, DNA methylation, and noncoding RNAs. Epigenetics, in turn, determines the gut microbial composition and thus influences the risk of developing CRC. This review discusses the complex crosstalk between metabolic reprogramming, gut microbiota, and epigenetics in CRC and highlights the potential applications of the gut microbiota as a biomarker for the prevention, diagnosis, and therapy of CRC.

Keywords: colorectal cancer; epigenetics; gut microbes; metabolic reprogramming; obesity

DOI: https://doi.org/10.1093/carcin/bgad058

Prostaglandins Leukot Essent Fatty Acids. 2023 Aug 09. pii: S0952-3278(23)00054-6. [Epub ahead of print]196 102585

Tumor microenvironment-derived monoacylglycerol lipase provokes tumor-specific immune responses and lipid profiles.

Eva Gruden, Melanie Kienzl, Carina Hasenoehrl, Arailym Sarsembayeva, Dusica Ristic, Sophie Theresa Schmid, Kathrin Maitz, Ulrike Taschler, Lisa Hahnefeld, Robert Gurke, Dominique Thomas, Julia Kargl, Rudolf Schicho.

We recently described that monoacylglycerol lipase (MGL) is present in the tumor microenvironment (TME), increasing tumor growth. In this study we compare the implications of MGL deficiency in the TME in different tumor types. We show that subcutaneous injection of KP (KrasLSL-G12D/p53fl/fl, mouse lung adenocarcinoma) or B16-F10 cells (mouse melanoma) induced tumor growth in MGL wild type (WT) and knockout (KO) mice. MGL deficiency in the TME attenuated the growth of KP cell tumors whereas tumors from B16-F10 cells increased in size. Opposite immune cell profiles were detected between the two tumor types in MGL KO mice. In line with their anti-tumorigenic function, the number of CD8+ effector T cells and eosinophils increased in KP cell tumors of MGL KO vs. WT mice whereas their presence was reduced in B16-F10 cell tumors of MGL KO mice. Differences were seen in lipid profiles between the investigated tumor types. 2-arachidonoylglycerol (2-AG) content significantly increased in KP, but not B16-F10 cell tumors of MGL KO vs. WT mice while other endocannabinoid-related lipids remained unchanged. However, profiles of phospho- and lysophospholipids, sphingomyelins and fatty acids in KP cell tumors were clearly distinct to those measured in B16-F10 cell tumors. Our data indicate that TME-localized MGL impacts tumor growth, as well as levels of 2-AG and other lipids in a tumor specific manner.

Keywords: (lyso)phospholipids; Endocannabinoids; Melanoma; Monoacylglycerol lipase; Non-small cell lung cancer; Tumor microenvironment

DOI: https://doi.org/10.1016/j.plefa.2023.102585

Curr Med Chem. 2023 Aug 18.

Heterogeneity of lipid metabolism and its clinical and immune correlation in lung adenocarcinoma.

Xugang Zhang, Weiqing Li, Taorui Liu, Huiqin Guo, Qianqian Sun, Baozhong Li.

INTRODUCTION: The role of lipid metabolism in lung adenocarcinoma (LUAD) is not completely researched. Lipid metabolism reprogramming is a characteristic of malignancies and contributes to carcinogenesis and progression. The transcriptome and scRNA-seq data and clinical information were downloaded from the public databases.METHOD: Lipid metabolism pathways were collected from the MSigDB database, and molecular subtypes were classified based on lipid metabolism features via consensus clustering. The bidirectional crosstalk between immune cells and malignant cells was analyzed. Differences in lipid metabolism at the single-cell level and their correlation with the tumor microenvironment (TME) were also studied. LUAD patients were classified into two subtypes, showing distinct mutation and lipid metabolism features based on lipid metabolism characteristics. Meanwhile, significant differences in the overall survival, clinical characteristics, and immune landscape were observed between the two subtypes. We also found that clust1 had higher oxidative stress status. There were 116 differentially expressed genes between the two subtypes, which were significantly associated with cell cycle progression. We identified 4001 immune cells, including 483 malignant cells and 3518 normal cells, and found active intercellular communication and significant differences in lipid metabolism characteristics between the malignant cells and normal cells. Furthermore, several lipid metabolism pathways were found to be associated with TME factors, including hypoxia and angiogenesis.
RESULT: The current findings indicated that lipid metabolism was involved in the development and cellular heterogeneity of LUAD and revealed widespread reprogramming across multiple cellular elements in the TME of LUAD.
CONCLUSION: This characterization improved the current understanding of tumor biology and enabled the identification of novel targets for immunotherapy.

Keywords: Lipid metabolism reprogramming; consensus clustering; immune; intercellular communication; lung adenocarcinoma; oxidative stress; tumor microenvironment

DOI: https://doi.org/10.2174/0929867331666230818144416