1. Functional discovery of targetable dependencies in recurrent glioblastoma
- Author
-
Sheila Singh, Chirayu Chokshi, David Tieu, Kevin Brown, Chitra Venugopal, Martin Rossotti, Katherine Chan, Amy Tong, Laura Kuhlmann, Lina Liu, Benjamin Brakel, Vaseem Shaikh, William Maich, Yujin Suk, Daniel Mobilio, Neil Savage, Nikoo Aghaei, Minomi Subapanditha, Dillon McKenna, Vladimir Ignatchenko, Joseph Salamoun, Peter Wipf, Elizabeth Sharlow, John Provias, Jian-Qiang Lu, Naresh Murty, John Lazo, Thomas Kislinger, Kevin Henry, Yu Lu, and Jason Moffat
- 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 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. Mechanistically, genetic perturbation or small molecule inhibition of PTP4A2 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 also mimic the effects of PTP4A2 inhibition. We conclude that functional reprogramming drives tumorigenicity and dependence on a multi-targetable PTP4A2-ROBO1 signaling axis at GBM recurrence.
- Published
- 2022