Metabolic regulation of the glioblastoma stem cell epitranscriptome by malate dehydrogenase 2.

in Cell metabolism by Deguan Lv, Deobrat Dixit, Andrea F Cruz, Leo J Y Kim, Likun Duan, Xin Xu, Qiulian Wu, Cuiqing Zhong, Chenfei Lu, Zachary C Gersey, Ryan C Gimple, Qi Xie, Kailin Yang, Xiaojing Liu, Xiaoguang Fang, Xujia Wu, Reilly L Kidwell, Xiuxing Wang, Shideng Bao, Housheng H He, Jason W Locasale, Sameer Agnihotri, Jeremy N Rich

TLDR

  • The study investigates how cancer cells change their metabolism to survive and grow. The study found that glioblastoma (GBM) stem cells (GSCs) have a higher activity of a metabolic pathway called the malate-aspartate shuttle (MAS) and express a protein called malate dehydrogenase 2 (MDH2).
  • The study used genetic and drug treatments to reduce the activity of MDH2 in GSCs, which slowed down their growth and reduced their ability to form tumors. The study also found that MDH2 affects the way RNA molecules are modified, which can impact the activity of certain proteins in the cells. The study also found that a drug called dasatinib, which is used to treat some types of cancer, worked better when used with MDH2 inhibition. The primary goal of the study was to understand how GSCs change their metabolism and how this affects their growth and ability to form tumors, and to identify potential treatments for GBM.

Abstract

Tumors reprogram their metabolism to generate complex neoplastic ecosystems. Here, we demonstrate that glioblastoma (GBM) stem cells (GSCs) display elevated activity of the malate-aspartate shuttle (MAS) and expression of malate dehydrogenase 2 (MDH2). Genetic and pharmacologic targeting of MDH2 attenuated GSC proliferation, self-renewal, and in vivo tumor growth, partially rescued by aspartate. Targeting MDH2 induced accumulation of alpha-ketoglutarate (αKG), a critical co-factor for dioxygenases, including the N6-methyladenosine (m6A) RNA demethylase AlkB homolog 5, RNA demethylase (ALKBH5). Forced expression of MDH2 increased m6A levels and inhibited ALKBH5 activity, both rescued by αKG supplementation. Reciprocally, targeting MDH2 reduced global m6A levels with platelet-derived growth factor receptor-β (PDGFRβ) as a regulated transcript. Pharmacological inhibition of MDH2 in GSCs augmented efficacy of dasatinib, an orally bioavailable multi-kinase inhibitor, including PDGFRβ. Collectively, stem-like tumor cells reprogram their metabolism to induce changes in their epitranscriptomes and reveal possible therapeutic paradigms.

Overview

  • The study investigates the metabolic reprogramming of glioblastoma (GBM) stem cells (GSCs) and its impact on their epitranscriptomes. The study demonstrates that GSCs display elevated activity of the malate-aspartate shuttle (MAS) and expression of malate dehydrogenase 2 (MDH2).
  • The study uses genetic and pharmacologic targeting of MDH2 to attenuate GSC proliferation, self-renewal, and in vivo tumor growth, partially rescued by aspartate. The study also explores the role of MDH2 in regulating the epitranscriptome of GSCs and its impact on the activity of dioxygenases, including the N6-methyladenosine (m6A) RNA demethylase AlkB homolog 5, RNA demethylase (ALKBH5).
  • The primary objective of the study is to investigate the metabolic reprogramming of GSCs and its impact on their epitranscriptomes. The study aims to identify potential therapeutic paradigms for GBM.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions or interventions, including genetic and pharmacologic targeting of MDH2, aspartate supplementation, and dasatinib treatment. The study identifies significant differences or similarities in the results between these conditions, such as reduced GSC proliferation, self-renewal, and in vivo tumor growth, and increased m6A levels and ALKBH5 activity with MDH2 targeting. The study also finds that MDH2 targeting reduces global m6A levels with PDGFRβ as a regulated transcript, and pharmacological inhibition of MDH2 augments the efficacy of dasatinib, including PDGFRβ. The key findings of the study suggest that stem-like tumor cells reprogram their metabolism to induce changes in their epitranscriptomes and reveal possible therapeutic paradigms for GBM.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice, as they provide insights into the metabolic reprogramming of GSCs and its impact on their epitranscriptomes. The study identifies potential therapeutic paradigms for GBM, such as targeting MDH2 and dasatinib. The study also highlights the importance of understanding the metabolic reprogramming of tumor cells and its impact on their epitranscriptomes for developing effective therapies. Future research directions could include exploring the role of other metabolic pathways in GSCs and their epitranscriptomes, investigating the efficacy of other drugs in combination with MDH2 targeting, and developing personalized therapies based on the metabolic reprogramming of individual tumors.
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