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

• Published in: Advanced science 2023-07, Vol.10 (20), p.e2205949-n/a
• Main Authors: Wang, Tao, Zhou, Yunxia, Fan, Yunping, Duan, Hao, Guo, Xiaoyu, Chang, Jinlong, Jiang, Youheng, Li, Changxue, Fu, Zhang, Gao, Yunfei, Guo, Xiaoran, Sidlauskas, Kastytis, He, Zhenqiang, Da Costa, Clive, Sheng, Xia, Wu, Dinglan, Yuan, Jinqiu, Li, Huiliang, He, Yulong, Mou, Yonggao, Li, Ningning
• Format: Article
• Language: English
• Subjects: Apoptosis; Brain cancer; Cell growth; Cholesterol; Cytokines; Gene expression; glioma; glioma‐associated microglia/macrophages; Homeostasis; Kinases; Metabolism; Metabolites; MicroRNAs; Morphology; Mutation; Sterols; Transcription factors; tumor microenvironment
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202205949

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. The authors demonstrate that excessive cholesterol excreted from Isocitrate dehydrogenase (IDH) ‐mutant glioma cells, as a metabolic messenger, determines M1‐like polarization of glioma‐associated microglia/macrophage (GAMs). This study reveals that the remodeling of GAM phenotypes results from the alteration of tumoral cholesterol homeostasis via IDH mutation‐induced PERK activation, highlighting PERK as a promising therapeutic target for the treatment of glioma.