Author ORCID Identifier

0000-0002-1999-8494

Date of Graduation

8-2017

Document Type

Dissertation (PhD)

Program Affiliation

Genes and Development

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Giulio F. Draetta, M.D., Ph.D.

Committee Member

Russell Broaddus, M.D., Ph.D.

Committee Member

Sadhan Majumder, Ph.D.

Committee Member

Alfred Yung, M.D.

Committee Member

Ralf Krahe, Ph.D.

Abstract

Despite current multimodal therapies for glioblastoma (GBM) the prognosis remains very grim. There is a tremendous need to identify new genetic drivers 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 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 resulted in a paradigm shift in our current understanding of WISP1 as merely a secreted extracellular matrix protein as we have shown here that it can drive GBM in a non-canonical manner in the cytosol.

Keywords

functional genomics, oncogene, glioblastoma, driver, gain-of-function screen

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