bims-mecami 2023-04-09 papers

Issue of 2023–04–09
five papers selected by
Oltea Sampetrean, Keio University

Antioxid Redox Signal. 2023 Apr 05.

Glioblastomas: Hijacking Metabolism to Build a Flexible Shield for Therapy Resistance.

Significance: Glioblastomas (GBMs) are among the most lethal tumors despite the almost exclusive localization to the brain. This is largely due to therapeutic resistance. Radiation and chemotherapy significantly increase the survival for GBM patients, however, GBMs always recur, and the median overall survival is just over a year. Proposed reasons for such intractable resistance to therapy are numerous and include tumor metabolism, in particular, the ability of tumor cells to reconfigure metabolic fluxes on demand (metabolic plasticity). Understanding how the hard-wired, oncogene-driven metabolic tendencies of GBMs intersect with flexible, context-induced metabolic rewiring promises to reveal novel approaches for combating therapy resistance. Recent Advances: Personalized genome-scale metabolic flux models have recently provided evidence that metabolic flexibility promotes radiation resistance in cancer and identified tumor redox metabolism as a major predictor for resistance to radiation therapy (RT). It was demonstrated that radioresistant tumors, including GBM, reroute metabolic fluxes to boost the levels of reducing factors of the cell, thus enhancing clearance of reactive oxygen species that are generated during RT and promoting survival. Critical Issues: The current body of knowledge from published studies strongly supports the notion that robust metabolic plasticity can act as a (flexible) shield against the cytotoxic effects of standard GBM therapies, thus driving therapy resistance. The limited understanding of the critical drivers of such metabolic plasticity hampers the rational design of effective combination therapies. Future Directions: Identifying and targeting regulators of metabolic plasticity, rather than specific metabolic pathways, in combination with standard-of-care treatments have the potential to improve therapeutic outcomes in GBM.

Keywords: glioblastoma; metabolism; plasticity; redox

DOI: https://doi.org/10.1089/ars.2022.0088

Front Cell Dev Biol. 2023 ;11 1141215

The impact of microbiome dysbiosis on T cell function within the tumor microenvironment (TME).

Michelle P DiPalma, Joseph N Blattman.

Insights into the effect of the microbiome's composition on immune cell function have recently been discerned and further characterized. Microbiome dysbiosis can result in functional alterations across immune cells, including those required for innate and adaptive immune responses to malignancies and immunotherapy treatment. Dysbiosis can yield changes in or elimination of metabolite secretions, such as short-chain fatty acids (SCFAs), from certain bacterial species that are believed to impact proper immune cell function. Such alterations within the tumor microenvironment (TME) can significantly affect T cell function and survival necessary for eliminating cancerous cells. Understanding these effects is essential to improve the immune system's ability to fight malignancies and the subsequent efficacy of immunotherapies that rely on T cells. In this review, we assess typical T cell response to malignancies, classify the known impact of the microbiome and particular metabolites on T cells, discuss how dysbiosis can affect their function in the TME then further describe the impact of the microbiome on T cell-based immunotherapy treatment, with an emphasis on recent developments in the field. Understanding the impact of dysbiosis on T cell function within the TME can carry substantial implications for the design of immunotherapy treatments and further our understanding of factors that could impact how the immune system combats malignancies.

Keywords: T cell; T cell signaling; dysbiosis; immunotherapy; metabolites; microbiome; short chain fatty acids (SCFAs); tumor microenvironment (TME)

DOI: https://doi.org/10.3389/fcell.2023.1141215

Biochim Biophys Acta Rev Cancer. 2023 Apr 02. pii: S0304-419X(23)00042-2. [Epub ahead of print] 188893

The role of amino acid metabolism alterations in pancreatic cancer: From mechanism to application.

Shenao Fu, Shaokang Xu, Shubing Zhang.

The incidence of pancreatic cancer is increasing in both developed and developing Nations. In recent years, various research evidence suggested that reprogrammed metabolism may play a key role in pancreatic cancer tumorigenesis and development. Therefore, it has great potential as a diagnostic, prognostic and therapeutic target. Amino acid metabolism is deregulated in pancreatic cancer, and changes in amino acid metabolism can affect cancer cell status, systemic metabolism in malignant tumor patients and mistakenly involved in different biological processes including stemness, proliferation and growth, invasion and migration, redox state maintenance, autophagy, apoptosis and even tumor microenvironment interaction. Generally, the above effects are achieved through two pathways, energy metabolism and signal transduction. This review aims to highlight the current research progress on the abnormal alterations of amino acids metabolism in pancreatic cancer, how they affect tumorigenesis and development of pancreatic cancer and the application prospects of them as diagnostic, prognostic and therapeutic targets.

Keywords: Amino acid metabolism; Apoptosis; Autophagy; Cellular redox homeostasis; Pancreatic cancer; Tumor microenvironment; mTOR signaling

DOI: https://doi.org/10.1016/j.bbcan.2023.188893

Front Immunol. 2023 ;14 1095195

A chemokine network of T cell exhaustion and metabolic reprogramming in renal cell carcinoma.

Renate Pichler, Peter J Siska, Piotr Tymoszuk, Agnieszka Martowicz, Gerold Untergasser, Roman Mayr, Florian Weber, Andreas Seeber, Florian Kocher, Dominik A Barth, Martin Pichler, Martin Thurnher.

Renal cell carcinoma (RCC) is frequently infiltrated by immune cells, a process which is governed by chemokines. CD8+ T cells in the RCC tumor microenvironment (TME) may be exhausted which most likely influence therapy response and survival. The aim of this study was to evaluate chemokine-driven T cell recruitment, T cell exhaustion in the RCC TME, as well as metabolic processes leading to their functional anergy in RCC. Eight publicly available bulk RCC transcriptome collectives (n=1819) and a single cell RNAseq dataset (n=12) were analyzed. Immunodeconvolution, semi-supervised clustering, gene set variation analysis and Monte Carlo-based modeling of metabolic reaction activity were employed. Among 28 chemokine genes available, CXCL9/10/11/CXCR3, CXCL13/CXCR5 and XCL1/XCR1 mRNA expression were significantly increased in RCC compared to normal kidney tissue and also strongly associated with tumor-infiltrating effector memory and central memory CD8+ T cells in all investigated collectives. M1 TAMs, T cells, NK cells as well as tumor cells were identified as the major sources of these chemokines, whereas T cells, B cells and dendritic cells were found to predominantly express the cognate receptors. The cluster of RCCs characterized by high chemokine expression and high CD8+ T cell infiltration displayed a strong activation of IFN/JAK/STAT signaling with elevated expression of multiple T cell exhaustion-associated transcripts. Chemokinehigh RCCs were characterized by metabolic reprogramming, in particular by downregulated OXPHOS and increased IDO1-mediated tryptophan degradation. None of the investigated chemokine genes was significantly associated with survival or response to immunotherapy. We propose a chemokine network that mediates CD8+ T cell recruitment and identify T cell exhaustion, altered energy metabolism and high IDO1 activity as key mechanisms of their suppression. Concomitant targeting of exhaustion pathways and metabolism may pose an effective approach to RCC therapy.

Keywords: IDO, biomarker; OXPHOS; RCC; T cells; chemokines; immunotherapy; metabolism

DOI: https://doi.org/10.3389/fimmu.2023.1095195

Proc Natl Acad Sci U S A. 2023 Apr 11. 120(15): e2209435120

The moonlighting function of glycolytic enzyme enolase-1 promotes choline phospholipid metabolism and tumor cell proliferation.

Qingxia Ma, Hongfei Jiang, Leina Ma, Gaoxiang Zhao, Qianqian Xu, Dong Guo, Ningning He, Hao Liu, Zhaoyuan Meng, Juanjuan Liu, Lei Zhu, Qian Lin, Xiaolin Wu, Min Li, Shudi Luo, Jing Fang, Zhimin Lu.

Aberrantly upregulated choline phospholipid metabolism is a novel emerging hallmark of cancer, and choline kinase α (CHKα), a key enzyme for phosphatidylcholine production, is overexpressed in many types of human cancer through undefined mechanisms. Here, we demonstrate that the expression levels of the glycolytic enzyme enolase-1 (ENO1) are positively correlated with CHKα expression levels in human glioblastoma specimens and that ENO1 tightly governs CHKα expression via posttranslational regulation. Mechanistically, we reveal that both ENO1 and the ubiquitin E3 ligase TRIM25 are associated with CHKα. Highly expressed ENO1 in tumor cells binds to I199/F200 of CHKα, thereby abrogating the interaction between CHKα and TRIM25. This abrogation leads to the inhibition of TRIM25-mediated polyubiquitylation of CHKα at K195, increased stability of CHKα, enhanced choline metabolism in glioblastoma cells, and accelerated brain tumor growth. In addition, the expression levels of both ENO1 and CHKα are associated with poor prognosis in glioblastoma patients. These findings highlight a critical moonlighting function of ENO1 in choline phospholipid metabolism and provide unprecedented insight into the integrated regulation of cancer metabolism by crosstalk between glycolytic and lipidic enzymes.

Keywords: CHKα; TRIM25; enolase

DOI: https://doi.org/10.1073/pnas.2209435120