Chronic AMPK inactivation slows SHH medulloblastoma progression by inhibiting mTORC1 signaling and depleting tumor stem cells
Daniel Shiloh Malawsky,
Taylor Dismuke,
Hedi Liu,
Ethan Castellino,
Jay Brenman,
Biplab Dasgupta,
Andrey Tikunov,
Timothy R. Gershon
Affiliations
Daniel Shiloh Malawsky
Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
Taylor Dismuke
Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
Hedi Liu
Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
Ethan Castellino
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
Jay Brenman
Department of Cell Biology and Physiology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
Biplab Dasgupta
Division of Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
Andrey Tikunov
Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA; Children’s Center for Neurosciences Research, Children’s Hospital of Atlanta, Emory University, Atlanta, GA 30322, USA
Timothy R. Gershon
Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA; Children’s Center for Neurosciences Research, Children’s Hospital of Atlanta, Emory University, Atlanta, GA 30322, USA; Corresponding author
Summary: 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.
