SYST-28 FUNCTIONAL MAPPING REVEALS WIDESPREAD REMODELLING AND A NOVEL TARGETABLE PTP4A2-ROBO1 SIGNALING AXIS AT GLIOBLASTOMA RECURRENCE
نویسندگان
چکیده
Abstract Resistance to genotoxic therapies and tumor recurrence are hallmarks of glioblastoma (GBM), an aggressive brain tumor. Here, we explore the functional drivers post-treatment recurrent GBM. By conducting genome-wide CRISPR-Cas9 screens in patient-derived GBM models, uncover distinct genetic dependencies cells that were absent their patient-matched primary predecessors, accompanied by increased mutational burden differential transcript protein expression. These analyses map a multilayered response drive recurrence, identifying tyrosine phosphatase 4A2 (PTP4A2) as novel modulator self-renewal, proliferation tumorigenicity at recurrence. Mechanistically, perturbation or small molecule inhibition PTP4A2 represses axon guidance activity through dephosphorylation axis with roundabout receptor 1 (ROBO1), exploiting dependency on ROBO signaling. Roundabout (ROBO1) is involved axonal during neurodevelopment aberrant ROBO1 signaling associated higher was highly expressed surface malignant treatment-refractory initiating (BTICs) rGBM, metastasis (BM) medulloblastoma (MB). Importantly, engineered anti-ROBO1 single-domain antibodies also mimic effects inhibition. We therefore developed validated second-generation CAR-T against ROBO1, which demonstrated upregulation activation markers, enhanced cytokine release, markedly proliferation, induction potent specific cell death compared untransduced all three cancers. findings further vivo MB BM where showed significant reduction increase survival treated mice. conclude reprogramming drives dependence multi-targetable PTP4A2-ROBO1
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ژورنال
عنوان ژورنال: Neuro-oncology advances
سال: 2023
ISSN: ['2632-2498']
DOI: https://doi.org/10.1093/noajnl/vdad070.130