| Title: |
STEM-05. FUNCTIONAL MAPPING REVEALS WIDESPREAD REMODELLING AND UNRECOGNIZED PATHWAY DEPENDENCIES IN RECURRENT GLIOBLASTOMA |
| 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 |
| Source: |
Neuro-Oncology ; volume 23, issue Supplement_6, page vi22-vi22 ; ISSN 1522-8517 1523-5866 |
| Publisher Information: |
Oxford University Press (OUP) |
| Publication Year: |
2021 |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1093/neuonc/noab196.081 |
| Availability: |
https://doi.org/10.1093/neuonc/noab196.081; https://academic.oup.com/neuro-oncology/article-pdf/23/Supplement_6/vi22/41140186/noab196.081.pdf |
| Rights: |
https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model |
| Accession Number: |
edsbas.690B93AE |
| Database: |
BASE |