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  3. PERK-Mediated Cholesterol Excretion from IDH Mutant Glioma Determines Anti-Tumoral Polarization of Microglia

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

  • Adv Sci (Weinh). 2023 May 11;e2205949. doi: 10.1002/advs.202205949.
Tao Wang 1,  Yunxia Zhou 1,  Yunping Fan 1 2,  Hao Duan 3,  Xiaoyu Guo 3,  Jinlong Chang 1,  Youheng Jiang 1,  Changxue Li 1,  Zhang Fu 1,  Yunfei Gao 1 2,  Xiaoran Guo 1,  Kastytis Sidlauskas 4,  Zhenqiang He 3,  Clive Da Costa 5,  Xia Sheng 6,  Dinglan Wu 7,  Jinqiu Yuan 8,  Huiliang Li 9 10,  Yulong He 1 11,  Yonggao Mou 3,  Ningning Li 1 10
Affiliations

Affiliations

  • 1 Tomas Lindahl Nobel Laureate Laboratory, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, 518107, China.
  • 2 Department of Otolaryngology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, 518107, China.
  • 3 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.
  • 4 Barts Cancer Institute, Queen Mary University of London, London, London, EC1M 6BQ, United Kingdom.
  • 5 Biological Research Facility, The Francis Crick Institute, London, London, NW1 1AT, United Kingdom.
  • 6 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.
  • 7 Shenzhen Key Laboratory of Viral Oncology, The Clinical Innovation & Research Centre (CIRC), Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, 510086, China.
  • 8 Clinical Research Center, Big Data Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, 518107, China.
  • 9 Wolfson Institute for Biomedical Research, Division of Medicine, Faculty of Medical Sciences, University College London, London, London, WC1E, United Kingdom.
  • 10 China-UK Institute for Frontier Science, Shenzhen, Guangdong, 518000, China.
  • 11 Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, 518107, China.
PMID: 37166058 DOI: 10.1002/advs.202205949
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.

Keywords

cholesterol; glioma; glioma-associated microglia/macrophages; tumor microenvironment.

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