bims-mecami 2024-05-05 papers

bims-mecami

Biomed News

on Metabolic interactions between cancer cells and their microenvironment

Issue of 2024–05–05
seven papers selected by
Oltea Sampetrean, Keio University

Mitochondrial genome transfer drives metabolic reprogramming in adjacent colonic epithelial cells promoting TGFβ1-mediated tumor progression.
Targeting metabolism of breast cancer and its implications in T cell immunotherapy.
Cycling back to folate metabolism in cancer.
Metabolic reprogramming of tumor-associated macrophages using glutamine antagonist JHU083 drives tumor immunity in myeloid-rich prostate and bladder cancer tumors.
Immunometabolism of CD8+ T cell differentiation in cancer.
Abnormal changes in metabolites caused by m6A methylation modification: The leading factors that induce the formation of immunosuppressive tumor microenvironment and their promising potential for clinical application.
Acetate reprogrammes tumour metabolism and promotes PD-L1 expression and immune evasion by upregulating c-Myc.

Nat Commun. 2024 Apr 30. 15(1): 3653

Mitochondrial genome transfer drives metabolic reprogramming in adjacent colonic epithelial cells promoting TGFβ1-mediated tumor progression.

Bingjie Guan, Youdong Liu, Bowen Xie, Senlin Zhao, Abudushalamu Yalikun, Weiwei Chen, Menghua Zhou, Qi Gu, Dongwang Yan.

Although nontumor components play an essential role in colon cancer (CC) progression, the intercellular communication between CC cells and adjacent colonic epithelial cells (CECs) remains poorly understood. Here, we show that intact mitochondrial genome (mitochondrial DNA, mtDNA) is enriched in serum extracellular vesicles (EVs) from CC patients and positively correlated with tumor stage. Intriguingly, circular mtDNA transferred via tumor cell-derived EVs (EV-mtDNA) enhances mitochondrial respiration and reactive oxygen species (ROS) production in CECs. Moreover, the EV-mtDNA increases TGFβ1 expression in CECs, which in turn promotes tumor progression. Mechanistically, the intercellular mtDNA transfer activates the mitochondrial respiratory chain to induce the ROS-driven RelA nuclear translocation in CECs, thereby transcriptionally regulating TGFβ1 expression and promoting tumor progression via the TGFβ/Smad pathway. Hence, this study highlights EV-mtDNA as a major driver of paracrine metabolic crosstalk between CC cells and adjacent CECs, possibly identifying it as a potential biomarker and therapeutic target for CC.

DOI: https://doi.org/10.1038/s41467-024-48100-y
Front Immunol. 2024 ;15 1381970

Targeting metabolism of breast cancer and its implications in T cell immunotherapy.

Jialuo Zou, Cunjun Mai, Zhiqin Lin, Jian Zhou, Guie Lai.

  Breast cancer is a prominent health issue amongst women around the world. Immunotherapies including tumor targeted antibodies, adoptive T cell therapy, vaccines, and immune checkpoint blockers have rejuvenated the clinical management of breast cancer, but the prognosis of patients remains dismal. Metabolic reprogramming and immune escape are two important mechanisms supporting the progression of breast cancer. The deprivation uptake of nutrients (such as glucose, amino acid, and lipid) by breast cancer cells has a significant impact on tumor growth and microenvironment remodeling. In recent years, in-depth researches on the mechanism of metabolic reprogramming and immune escape have been extensively conducted, and targeting metabolic reprogramming has been proposed as a new therapeutic strategy for breast cancer. This article reviews the abnormal metabolism of breast cancer cells and its impact on the anti-tumor activity of T cells, and further explores the possibility of targeting metabolism as a therapeutic strategy for breast cancer.

Keywords:  T cell immunotherapy; amino acid; breast cancer; glucose; immune escape; lipid; metabolic reprogramming

DOI:  https://doi.org/10.3389/fimmu.2024.1381970
Nat Cancer. 2024 May 02.

Cycling back to folate metabolism in cancer.

Younghwan Lee, Karen H Vousden, Marc Hennequart.

Metabolic changes contribute to cancer initiation and progression through effects on cancer cells, the tumor microenvironment and whole-body metabolism. Alterations in serine metabolism and the control of one-carbon cycles have emerged as critical for the development of many tumor types. In this Review, we focus on the mitochondrial folate cycle. We discuss recent evidence that, in addition to supporting nucleotide synthesis, mitochondrial folate metabolism also contributes to metastasis through support of antioxidant defense, mitochondrial protein synthesis and the overflow of excess formate. These observations offer potential therapeutic opportunities, including the modulation of formate metabolism through dietary interventions and the use of circulating folate cycle metabolites as biomarkers for cancer detection.

DOI: https://doi.org/10.1038/s43018-024-00739-8
Cancer Immunol Res. 2024 May 03.

Metabolic reprogramming of tumor-associated macrophages using glutamine antagonist JHU083 drives tumor immunity in myeloid-rich prostate and bladder cancer tumors.

Monali Praharaj, Fan Shen, Alex J Lee, Liang Zhao, Thomas R Nirschl, Debebe Theodros, Alok K Singh, Xiaoxu Wang, Kenneth M Adusei, Kara A Lombardo, Raekwon A Williams, Laura A Sena, Elizabeth A Thompson, Ada Tam, Srinivasan Yegnasubramanian, Edward J Pearce, Robert D Leone, Jesse Alt, Rana Rais, Barbara S Slusher, Drew M Pardoll, Jonathan D Powell, Jelani C Zarif.

Glutamine metabolism in tumor microenvironments critically regulates anti-tumor immunity. Using glutamine-antagonist prodrug JHU083, we report potent tumor growth inhibition in urologic tumors by JHU083-reprogrammed tumor-associated macrophages (TAMs) and tumor-infiltrating monocytes (TIMs). We show JHU083-mediated glutamine antagonism in tumor microenvironments induces TNF, pro-inflammatory, and mTORC1 signaling in intratumoral TAM clusters. JHU083-reprogrammed TAMs also exhibit increased tumor cell phagocytosis and diminished pro-angiogenic capacities. In vivo inhibition of TAM glutamine consumption resulted in increased glycolysis, a broken TCA cycle, and purine metabolism disruption. Although the anti-tumor effect of glutamine antagonism on tumor-infiltrating T cells was moderate, JHU083 promoted a stem cell-like phenotype in CD8+ T cells and decreased Treg abundance. Finally, JHU083 caused a ubiquitous shutdown in glutamine utilizing metabolic pathways in tumor cells, leading to reduced HIF-1alpha, c-MYC phosphorylation, and induction of tumor cell apoptosis, all key anti-tumor features.

DOI: https://doi.org/10.1158/2326-6066.CIR-23-1105
Trends Cancer. 2024 Apr 30. pii: S2405-8033(24)00059-1. [Epub ahead of print]

Immunometabolism of CD8+ T cell differentiation in cancer.

Hao Shi, Sidi Chen, Hongbo Chi.

  CD8+ cytotoxic T lymphocytes (CTLs) are central mediators of tumor immunity and immunotherapies. Upon tumor antigen recognition, CTLs differentiate from naive/memory-like toward terminally exhausted populations with more limited function against tumors. Such differentiation is regulated by both immune signals, including T cell receptors (TCRs), co-stimulation, and cytokines, and metabolism-associated processes. These immune signals shape the metabolic landscape via signaling, transcriptional and post-transcriptional mechanisms, while metabolic processes in turn exert spatiotemporal effects to modulate the strength and duration of immune signaling. Here, we review the bidirectional regulation between immune signals and metabolic processes, including nutrient uptake and intracellular metabolic pathways, in shaping CTL differentiation and exhaustion. We also discuss the mechanisms underlying how specific nutrient sources and metabolite-mediated signaling events orchestrate CTL biology. Understanding how metabolic programs and their interplay with immune signals instruct CTL differentiation and exhaustion is crucial to uncover tumor-immune interactions and design novel immunotherapies.

Keywords:  T cell differentiation; TCR; antitumor function; cytokines; exhaustion; mitochondrial fitness

DOI:  https://doi.org/10.1016/j.trecan.2024.03.010
J Adv Res. 2024 Apr 25. pii: S2090-1232(24)00159-0. [Epub ahead of print]

Abnormal changes in metabolites caused by m6A methylation modification: The leading factors that induce the formation of immunosuppressive tumor microenvironment and their promising potential for clinical application.

Liang Zhao, Junchen Guo, Shasha Xu, Meiqi Duan, Baiming Liu, He Zhao, Yihan Wang, Haiyang Liu, Zhi Yang, Hexue Yuan, Xiaodi Jiang, Xiaofeng Jiang.

   BACKGROUND: N6-methyladenosine (m6A) RNA methylation modifications have been widely implicated in the metabolic reprogramming of various cell types within the tumor microenvironment (TME) and are essential for meeting the demands of cellular growth and maintaining tissue homeostasis, enabling cells to adapt to the specific conditions of the TME. An increasing number of research studies have focused on the role of m6A modifications in glucose, amino acid and lipid metabolism, revealing their capacity to induce aberrant changes in metabolite levels. These changes may in turn trigger oncogenic signaling pathways, leading to substantial alterations within the TME. Notably, certain metabolites, including lactate, succinate, fumarate, 2-hydroxyglutarate (2-HG), glutamate, glutamine, methionine, S-adenosylmethionine, fatty acids and cholesterol, exhibit pronounced deviations from normal levels. These deviations not only foster tumorigenesis, proliferation and angiogenesis but also give rise to an immunosuppressive TME, thereby facilitating immune evasion by the tumor.
AIM OF REVIEW: The primary objective of this review is to comprehensively discuss the regulatory role of m6A modifications in the aforementioned metabolites and their potential impact on the development of an immunosuppressive TME through metabolic alterations.
KEY SCIENTIFIC CONCEPTS OF REVIEW: This review aims to elaborate on the intricate networks governed by the m6A-metabolite-TME axis and underscores its pivotal role in tumor progression. Furthermore, we delve into the potential implications of the m6A-metabolite-TME axis for the development of novel and targeted therapeutic strategies in cancer research.

Keywords:  Cancer; Metabolites; Targeted therapy; Tumor immunosuppressive microenvironment; m(6)A

DOI:  https://doi.org/10.1016/j.jare.2024.04.016
Nat Metab. 2024 May 03.

Acetate reprogrammes tumour metabolism and promotes PD-L1 expression and immune evasion by upregulating c-Myc.

Juhong Wang, Yannan Yang, Fei Shao, Ying Meng, Dong Guo, Jie He, Zhimin Lu.

Acetate, a precursor of acetyl-CoA, is instrumental in energy production, lipid synthesis and protein acetylation. However, whether acetate reprogrammes tumour metabolism and plays a role in tumour immune evasion remains unclear. Here, we show that acetate is the most abundant short-chain fatty acid in human non-small cell lung cancer tissues, with increased tumour-enriched acetate uptake. Acetate-derived acetyl-CoA induces c-Myc acetylation, which is mediated by the moonlighting function of the metabolic enzyme dihydrolipoamide S-acetyltransferase. Acetylated c-Myc increases its stability and subsequent transcription of the genes encoding programmed death-ligand 1, glycolytic enzymes, monocarboxylate transporter 1 and cell cycle accelerators. Dietary acetate supplementation promotes tumour growth and inhibits CD8+ T cell infiltration, whereas disruption of acetate uptake inhibits immune evasion, which increases the efficacy of anti-PD-1-based therapy. These findings highlight a critical role of acetate promoting tumour growth beyond its metabolic role as a carbon source by reprogramming tumour metabolism and immune evasion, and underscore the potential of controlling acetate metabolism to curb tumour growth and improve the response to immune checkpoint blockade therapy.

DOI: https://doi.org/10.1038/s42255-024-01037-4