DataVXAdvanced SciencePaper
journal article·2023-07Open access

PERK‐Mediated Cholesterol Excretion from IDH Mutant Glioma Determines Anti‐Tumoral Polarization of Microglia

Tao Wang, Yunxia Zhou, Yunping Fan, Hao Duan, Xiaoyu Guo, Jinlong Chang, Youheng Jiang, Changxue Li, Zhang Fu, Yunfei Gao, Xiaoran Guo, Kastytis Sidlauskas, Zhenqiang He, Clive Da Costa, Xia Sheng, Dinglan Wu, Jinqiu Yuan, Huiliang Li, Yulong He, Yonggao Mou, Ningning Li

Advanced Science· Volume 10· Issue 20
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Abstract

Abstract Isocitrate dehydrogenase (IDH) mutation, a known pathologic classifier, initiates metabolic reprogramming in glioma cells and has been linked to the reaction status of glioma‐associated microglia/macrophages (GAMs). However, it remains unclear how IDH genotypes contribute to GAM phenotypes. Here, it is demonstrated that gliomas expressing mutant IDH determine M1‐like polarization of GAMs, while archetypal IDH induces M2‐like polarization. Intriguingly, IDH‐mutant gliomas secrete excess cholesterol, resulting in cholesterol‐rich, pro‐inflammatory GAMs without altering their cholesterol biosynthesis, and simultaneously exhibiting low levels of tumoral cholesterol due to expression remodeling of cholesterol transport molecules, particularly upregulation of ABCA1 and downregulation of LDLR. Mechanistically, a miR‐19a/LDLR axis‐mediated novel post‐transcriptional regulation of cholesterol uptake is identified, modulated by IDH mutation, and influencing tumor cell proliferation and invasion. IDH mutation‐induced PERK activation enhances cholesterol export from glioma cells via the miR‐19a/LDLR axis and ABCA1/APOE upregulation. Further, a synthetic PERK activator, CCT020312 is introduced, which markedly stimulates cholesterol efflux from IDH wild‐type glioma cells, induces M1‐like polarization of GAMs, and consequently suppresses glioma cell invasion. The findings reveal an essential role of the PERK/miR‐19a/LDLR signaling pathway in orchestrating gliomal cholesterol transport and the subsequent phenotypes of GAMs, thereby highlighting a novel potential target pathway for glioma therapy.
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Research context

OpenAlex topics: Immune cells in cancer · interferon and immune responses · Cancer-related molecular mechanisms research

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Affiliations

Tomas Lindahl Nobel Laureate Laboratory The Seventh Affiliated Hospital of Sun Yat‐sen University Shenzhen Guangdong 518107 China

Department of Otolaryngology The Seventh Affiliated Hospital of Sun Yat‐sen University Shenzhen Guangdong 518107 China

Department of Neurosurgery State Key Laboratory of Oncology in South China & Collaborative Innovation Center for Cancer Medicine Sun Yat‐sen University Cancer Centre Guangzhou Guangdong 510060 China

Barts Cancer Institute Queen Mary University of London London London EC1M 6BQ United Kingdom

Biological Research Facility The Francis Crick Institute London London NW1 1AT United Kingdom

Ministry of Education Key Lab of Environment and Health School of Public Health Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei 430030 China

Shenzhen Key Laboratory of Viral Oncology The Clinical Innovation & Research Centre (CIRC) Shenzhen Hospital Southern Medical University Shenzhen Guangdong 510086 China

Clinical Research Center Big Data Center The Seventh Affiliated Hospital of Sun Yat‐sen University Shenzhen Guangdong 518107 China

Wolfson Institute for Biomedical Research Division of Medicine Faculty of Medical Sciences University College London London London WC1E United Kingdom

China‐UK Institute for Frontier Science Shenzhen Guangdong 518000 China

Guangdong Provincial Key Laboratory of Digestive Cancer Research The Seventh Affiliated Hospital of Sun Yat‐sen University Shenzhen Guangdong 518107 China

Funding

National Natural Science Foundation of China · Sanming Project of Medicine in Shenzhen

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