Patrick DeSouza
Program: Computational and Systems Biology
Current advisor: Albert H. Kim, MD, PhD
Undergraduate university: Boston University
Research summary
Glioblastoma (GBM) is an aggressive, incurable brain tumor driven by heterogeneity between tumor cell-intrinsic and -extrinsic states for 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 in vivo tumors that recapitulate GBM. Tumor cell evolution began with stress-related metabolic changes and transitioned toward neuronal progenitor networks driven by transcription factor INSM1, which is highly expressed in human GBM tumors and intermediate progenitor cells during development that give rise to neuronal progenitors. Remarkably, inhibiting INSM1 in triple mutant NSCs caused reversal of oncogenic gene expression and functions to those of non-tumorigenic wildtype NSCs. These findings highlight the functional importance of an aberrant intermediate neuronal progenitor state in GBM pathogenesis.
Graduate publications
DeSouza PA, Qu X, Chen H, Patel B, Maher CA, Kim AH. 2021 Long, Noncoding RNA Dysregulation in Glioblastoma. Cancers (Basel), 13(7):1604..
Mahlokozera T, Patel B, Chen H, Desouza P, Qu X, Mao DD, Hafez D, Yang W, Taiwo R, Paturu M, Salehi A, Gujar AD, Dunn GP, Mosammaparast N, Petti AA, Yano H, Kim AH. 2021 Competitive binding of E3 ligases TRIM26 and WWP2 controls SOX2 in glioblastoma. Nat Commun, 12(1):6321.
DeSouza P, Qu X, Annamalai D, Maher C, Millman J, Kim AH. (2021). Dissecting the epigenetic mechanisms of TERT promoter mutant-driven tumor initiation using a human embryonic stem cell-derived model of glioblastoma. ., Abstract.