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| Status |
Public on Aug 07, 2024 |
| Title |
Functional mapping of Glioblastoma recurrence reveals targetable dependencies in an axonal guidance pathway in lethal brain cancers [Genome-wide CRISPR-Cas9] |
| Organism |
Homo sapiens |
| Experiment type |
Other
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| Summary |
Resistance to genotoxic therapies and tumor recurrence are hallmarks of glioblastoma (GBM), an aggressive brain tumor. Here, we explore functional drivers of post-treatment recurrent GBM. By conducting genome-wide CRISPR-Cas9 knockout screens in patient-derived GBM models, we uncover distinct genetic dependencies in recurrent tumor cells absent in their patient-matched primary predecessors, accompanied by increased mutational burden and differential transcript and protein expression. These analyses map a multilayered genetic response to drive tumor recurrence, identifying protein tyrosine phosphatase 4A2 (PTP4A2) as a novel modulator of self-renewal, proliferation and tumorigenicity at GBM recurrence. Genetic perturbation or small molecule inhibition of PTP4A2 activity represses axon guidance activity through a dephosphorylation axis with roundabout guidance receptor 1 (ROBO1), exploiting a functional dependency on ROBO signaling. Importantly, engineered anti-ROBO1 single-domain antibodies mimic effects of PTP4A2 inhibition. Since a pan-PTP4A inhibitor was limited by poor penetrance across the blood brain barrier (BBB) in vivo, a second-generation chimeric antigen receptor (CAR)-T cell therapy was engineered against ROBO1 that elicits specific and potent anti-tumor responses in vivo. A single dose of anti-ROBO1 CAR-T cells doubles median survival in patient-derived xenograft (PDX) models of recurrent glioblastoma, and also eradicates tumors in ~50% of mice in PDX models of adult lung-to-brain metastases and pediatric relapsed medulloblastoma. We conclude that functional reprogramming drives tumorigenicity and dependence on a multi-targetable PTP4A-ROBO1 signaling axis at GBM recurrence, with potential in other malignant brain tumors.
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| Overall design |
Genome-wide CRISPR-Cas9 screens were performed in primary and recurrent glioblastoma cell lines using the TKOv3 CRISPR library. Dropout profiles were compared to establish primary and recurrent cellular dependencies.
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| Contributor(s) |
Chokshi C, Brakel B, Brown KR, Moffat J, Singh S |
| Citation(s) |
39095594 |
| |
| Submission date |
Aug 08, 2023 |
| Last update date |
Aug 08, 2024 |
| Contact name |
Jason Moffat |
| E-mail(s) |
jason.moffat@sickkids.ca
|
| Organization name |
Hospital for Sick Children
|
| Department |
Genetics and Genome Biology
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| Lab |
Moffat
|
| Street address |
686 Bay Street
|
| City |
Toronto |
| State/province |
Ontario |
| ZIP/Postal code |
M5G0A4 |
| Country |
Canada |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (21)
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| This SubSeries is part of SuperSeries: |
| GSE240492 |
Functional mapping of Glioblastoma recurrence reveals targetable dependencies in an axonal guidance pathway in lethal brain cancers |
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| Relations |
| BioProject |
PRJNA1003542 |
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