Hexosaminidase B-driven cancer cell-macrophage co-dependency promotes glycolysis addiction and tumorigenesis in glioblastoma

Chen Zhu, Xin Chen, Tian-Qi Liu, Lin Cheng, Wen Cheng (), Peng Cheng () and An-Hua Wu ()
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Chen Zhu: Shengjing Hospital of China Medical University
Xin Chen: Shengjing Hospital of China Medical University
Tian-Qi Liu: Shengjing Hospital of China Medical University
Lin Cheng: The First Hospital of China Medical University
Wen Cheng: Shengjing Hospital of China Medical University
Peng Cheng: The First Hospital of China Medical University
An-Hua Wu: Shengjing Hospital of China Medical University

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Glycolytic metabolic reprogramming in cancer is regulated by both cancer intrinsic variations like isocitrate dehydrogenase 1 (IDH1) status and non-cancerous microenvironment components like tumor associated macrophages (TAMs). However, the detailed mechanism remains elusive. Here, we identify hexosaminidase B (HEXB) as a key regulator for glycolysis in glioblastoma (GBM). HEXB intercellularly manipulates TAMs to promote glycolysis in GBM cells, while intrinsically enhancing cancer cell glycolysis. Mechanistically, HEXB elevation augments tumor HIF1α protein stability through activating ITGB1/ILK/YAP1; Subsequently, HIF1α promotes HEXB and multiple glycolytic gene transcription in GBM cells. Genetic ablation and pharmacological inhibition of HEXB elicits substantial therapeutic effects in preclinical GBM models, while targeting HEXB doesn’t induce significant reduction in IDH1 mutant glioma and inhibiting IDH1 mutation-derived 2-hydroxyglutaric acid (2-HG) significantly restores HEXB expression in glioma cells. Our work highlights a HEXB driven TAMs-associated glycolysis-promoting network in GBM and provides clues for developing more effective therapies against it.

Date: 2024
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DOI: 10.1038/s41467-024-52888-0

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