Glioma-induced alterations in excitatory neurons are reversed by mTOR inhibition

Alexander R Goldberg; Athanassios Dovas; Daniela Torres; Brianna Pereira; Ashwin Viswanathan; Sohani Das Sharma; Angeliki Mela; Edward M Merricks; Cristina Megino-Luque; Julie J McInvale; Markel Olabarria; Leila Abrishami Shokooh; Hanzhi T Zhao; Cady Chen; Corina Kotidis; Peter Calvaresi; Matei A Banu; Aida Razavilar; Tejaswi D Sudhakar; Ankita Saxena; Cole Chokran; Nelson Humala; Aayushi Mahajan; Weihao Xu; Jordan B Metz; Eric A Bushong; Daniela Boassa; Mark H Ellisman; Elizabeth M C Hillman; Gunnar Hargus; Jose Javier Bravo-Cordero; Guy M McKhann 2nd; Brian J A Gill; Steven S Rosenfeld; Catherine A Schevon; Jeffrey N Bruce; Peter A Sims; Darcy S Peterka; Peter Canoll

doi:10.1016/j.neuron.2024.12.026

Glioma-induced alterations in excitatory neurons are reversed by mTOR inhibition

Neuron. 2025 Jan 16:S0896-6273(24)00926-7. doi: 10.1016/j.neuron.2024.12.026. Online ahead of print.

Authors

Alexander R Goldberg¹, Athanassios Dovas¹, Daniela Torres¹, Brianna Pereira¹, Ashwin Viswanathan¹, Sohani Das Sharma², Angeliki Mela¹, Edward M Merricks³, Cristina Megino-Luque⁴, Julie J McInvale¹, Markel Olabarria¹, Leila Abrishami Shokooh³, Hanzhi T Zhao⁵, Cady Chen¹, Corina Kotidis⁶, Peter Calvaresi¹, Matei A Banu⁶, Aida Razavilar¹, Tejaswi D Sudhakar¹, Ankita Saxena¹, Cole Chokran¹, Nelson Humala⁶, Aayushi Mahajan⁶, Weihao Xu⁵, Jordan B Metz², Eric A Bushong⁷, Daniela Boassa⁷, Mark H Ellisman⁷, Elizabeth M C Hillman⁵, Gunnar Hargus¹, Jose Javier Bravo-Cordero⁴, Guy M McKhann 2nd⁶, Brian J A Gill⁶, Steven S Rosenfeld⁸, Catherine A Schevon³, Jeffrey N Bruce⁶, Peter A Sims⁹, Darcy S Peterka¹⁰, Peter Canoll¹¹

Affiliations

¹ Department of Pathology and Cell Biology, Irving Cancer Research Center, Columbia University Irving Medical Center, New York, NY 10032, USA.
² Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA.
³ Department of Neurology, Columbia University Irving Medical Center, New York, NY 10032, USA.
⁴ Department of Medicine, Division of Hematology and Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10027, USA.
⁵ Laboratory for Functional Optical Imaging, Zuckerman Mind Brain Behavior Institute, Departments of Biomedical Engineering and Radiology, Columbia University, New York, NY 10027, USA.
⁶ Department of Neurological Surgery, Columbia University Irving Medical Center, New York, NY 10032, USA.
⁷ National Center for Microscopy and Imaging Research, University of California, San Diego, La Jolla, CA 92093, USA.
⁸ Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA.
⁹ Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA; Sulzberger Columbia Genome Center, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Biochemistry & Molecular Biophysics, Columbia University Irving Medical Center, New York, NY 10032, USA.
¹⁰ Irving Institute for Cancer Dynamics, Columbia University, New York, NY 10027, USA; Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA.
¹¹ Department of Pathology and Cell Biology, Irving Cancer Research Center, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Neurological Surgery, Columbia University Irving Medical Center, New York, NY 10032, USA. Electronic address: [email protected].

PMID: 39837324
DOI: 10.1016/j.neuron.2024.12.026

Abstract

Gliomas are aggressive neoplasms that diffusely infiltrate the brain and cause neurological symptoms, including cognitive deficits and seizures. Increased mTOR signaling has been implicated in glioma-induced neuronal hyperexcitability, but the molecular and functional consequences have not been identified. Here, we show three types of changes in tumor-associated neurons: (1) downregulation of transcripts encoding excitatory and inhibitory postsynaptic proteins and dendritic spine development and upregulation of cytoskeletal transcripts via neuron-specific profiling of ribosome-bound mRNA, (2) marked decreases in dendritic spine density via light and electron microscopy, and (3) progressive functional alterations leading to neuronal hyperexcitability via in vivo calcium imaging. A single acute dose of AZD8055, a combined mTORC1/2 inhibitor, reversed these tumor-induced changes. These findings reveal mTOR-driven pathological plasticity in neurons at the infiltrative margin of glioma and suggest new strategies for treating glioma-associated neurological symptoms.

Keywords: alterations in neuronal activity; brain tumor microenvironment; brain tumors; dendritic spines; excitatory neurons; glioma; glioma microenvironment; glioma-associated neuronal alterations; glioma-induced plasticity; mTOR inhibition; neuronal hyperexcitability.