STEM-05. FUNCTIONAL MAPPING REVEALS WIDESPREAD REMODELLING AND UNRECOGNIZED PATHWAY DEPENDENCIES IN RECURRENT GLIOBLASTOMA. (12th November 2021)

• Record Type: Journal Article
• Authors: Chokshi, Chirayu R; Tieu, David; Brown, Kevin R; Venugopal, Chitra; Liu, Lina; Kuhlmann, Laura; Rossotti, Martin A; Chan, Katherine; Tong, Amy H Y; Savage, Neil; McKenna, Dillon; Aghaei, Nikoo; Subapanditha, Minomi; Vaseem Shaikh, Muhammad; Tatari, Nazanin; Brakel, Benjamin; Nachmani, Omri; Ignatchenko, Vladimir; Salamoun, Joseph M; Wipf, Peter; Sharlow, Elizabeth; Provias, John P; Lu, Jian-Qiang; Murty, Naresh K; Lazo, John S; Kislinger, Thomas; Henry, Kevin A; Lu, Yu; Moffat, Jason; Singh, Sheila K
• Is Part Of: Neuro-oncology. Volume 23: Supplement 6(2021)
• Page Start: vi22
• Page End: vi22
• Publication Date: 2021-11-12
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noab196.081
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Resistance to genotoxic therapies and tumor recurrence are hallmarks of glioblastoma (GBM), an aggressive brain tumor. Here, we explore the functional drivers of post-treatment recurrent GBM. By conducting genome-wide CRISPR-Cas9 screens in patient-derived GBM models, we uncover distinct genetic dependencies in recurrent tumor cells that were absent in their patient-matched primary predecessors, accompanied by increased mutational burden and differential transcript and protein expression. These analyses support parallel tumor-intrinsic mechanisms of treatment resistance which rely on acquisition of immunosuppressive capacity, including a defective mismatch repair pathway, ablation of PTEN activity, and a novel combination of de novo mutations in SWI/SNF components. We map a multilayered genetic and functional response to resist chemoradiotherapy and drive tumor recurrence, identifying protein tyrosine phosphatase 4A2 ( PTP4A2 ) as a novel driver of self-renewal, proliferation and tumorigenicity at GBM recurrence. Mechanistically, genetic perturbation and a small molecule inhibitor of PTP4A2 repress axon guidance activity through a dephosphorylation axis with roundabout guidance receptor 1 (ROBO1) and exploit a genetic dependency on ROBO signaling. Importantly, engineered anti-ROBO1 single-domain antibodies also mimic the effects of PTP4A2 inhibition. We conclude that functional reprogramming drives tumorigenicity and present a dependence on a PTP4A2-ROBO1 signaling axis at GBM recurrence.