LAUSR

There is a tremendous need to identify new genetic drivers of glioblastoma which can serve as potential therapeutic targets. In order to find new drivers, we leveraged genomic datasets to conduct a context specific in vivo functional genomic screen of overexpressed and/or amplified genes in GBM. We identified WISP1, a secreted extracellular matrix protein, to be an overexpressed driver in GBM. Overexpression of WISP1 was able to drive tumor growth in various in vivo models. Knockdown of WISP1 with shRNAs resulted in reduced colony formation in vitro and reduced tumor growth in vivo. Rescue experiments validated that the shRNAs were on target. Functional characterization of the protein revealed that the TSP module is necessary for the phenotype. Intriguingly, overexpression of WISP1 lacking the signal peptide module for secretion resulted in a strong phenotype. Co-culture and conditioned medium experiments further supported a secretion independent intracellular role of WISP1 in GBM. Though WISP1 is a secreted protein we have found some basal localization in the cytosol. Overall, we have revealed WISP1 to be a driver of GBM with possible therapeutic potential as a target. This study has expanded our understanding of WISP1 by supporting a new role as a driver in GBM which can function in a non-canonical manner in the cytosol. Overall, we have revealed WISP1 to be a driver of GBM with possible therapeutic potential as a target.