Chronic AMPK inactivation slows SHH medulloblastoma progression by inhibiting mTORC1 signaling and depleting tumor stem cells

• Type of Material: Article
• Authors: Daniel Shiloh Malawsky, University of North Carolina, Chapel Hill; Taylor Dismuke, University of North Carolina, Chapel Hill; Hedi Liu, University of North Carolina, Chapel Hill; Ethan Castellino, Emory University; Jay Brenman, University of North Carolina, Chapel Hill; Biplab Dasgupta, Cincinnati Children's Hospital Medical Center; Andrey P. Tikunov, Emory University; Timothy Gershon, Emory University
• Language: English
• Date: 2023-11-14
• Publisher: Elsevier
• Publication Version: Final Published Version
• Copyright Statement: © 2023 The Authors
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): https://doi.org/10.1016/j.isci.2023.108443
• Title of Journal or Parent Work: iScience
• Volume: 26
• Issue: 12
• Start Page: 108443
• Grant/Funding Information: We thank the UNC CGBID Histology Core, supported by P30 DK 034987 and the UNC Tissue Pathology Laboratory Core supported by NCI CA016086. T.D. was supported by NINDS (F31 NS120459). T.R.G. was supported by NINDS (R01NS088219, R01NS102627, R01NS106227)and by the UNC Department of Neurology Research Fund, and by a TTSA grant from the NCTRACS Institute, which is supported by the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, through Grant Award Number UL1TR002489.
• Keywords: Model organism; Cancer; Cell biology; Sequence analysis; Molecular biology
• Research Categories: Health Sciences, Oncology; Biology, Molecular; Biology, Cell

Abstract

We show that inactivating AMPK in a genetic medulloblastoma model depletes tumor stem cells and slows progression. In medulloblastoma, the most common malignant pediatric brain tumor, drug-resistant stem cells co-exist with transit-amplifying cells and terminally differentiated neuronal progeny. Prior studies show that Hk2-dependent glycolysis promotes medulloblastoma progression by suppressing neural differentiation. To determine how the metabolic regulator AMPK affects medulloblastoma growth and differentiation, we inactivated AMPK genetically in medulloblastomas. We bred conditional Prkaa1 and Prkaa2 deletions into medulloblastoma-prone SmoM2 mice and compared SmoM2-driven medulloblastomas with intact or inactivated AMPK. AMPK-inactivation increased event-free survival (EFS) and altered cellular heterogeneity, increasing differentiation and decreasing tumor stem cell populations. Surprisingly, AMPK-inactivation decreased mTORC1 activity and decreased Hk2 expression. Hk2 deletion similarly depleted medulloblastoma stem cells, implicating reduced glycolysis in the AMPK-inactivated phenotype. Our results show that AMPK inactivation disproportionately impairs medulloblastoma stem cell populations typically refractory to conventional therapies.