Abstract

Glioblastoma (GBM) is an aggressive brain tumor driven by the interplay between tumor cell-intrinsic and -extrinsic heterogeneity, enabling rapid evolution. To investigate how canonical GBM mutations promote functional plasticity, we developed an isogenic human neural stem cell (NSC) model of GBM by sequential addition of TERT promoter, TP53, and PDGFRA point mutations. TP53 loss-of-function increased TERT expression during serial mutagenesis, but only triple mutant NSCs reliably formed lethal brain tumors in vivo that recapitulate GBM. Tumor cell evolution triggered stress-related metabolic changes and transitioned toward a neuronal progenitor network driven by transcription factor INSM1. INSM1 is highly expressed in human GBM tumors and, during cortical development, in intermediate progenitor cells (IPC), which give rise to neurons. Remarkably, INSM1 knockdown in triple mutant NSCs and primary GBM cells disrupted oncogenic gene expression and function and inhibited the in vivo tumorigenicity of triple mutant NSCs, highlighting the functional importance of an IPC-like cell state in GBM pathogenesis.

Committee Chair

Albert Kim

Committee Members

Christopher Maher; Jeffrey Millman; Luis Batista; Ting Wang

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Computational & Systems Biology)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

5-5-2025

Language

English (en)

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