Author ORCID Identifier

https://orcid.org/0000-0003-2043-9590

Date of Graduation

5-2021

Document Type

Dissertation (PhD)

Program Affiliation

Experimental Therapeutics

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

David McConkey

Committee Member

Pierre McCrea

Committee Member

Joya Chandra

Committee Member

Anirban Maitra

Committee Member

Varsha Gandhi

Abstract

Bladder cancer (BC) progression is measured by the degree of tumor cell invasion into the bladder wall and dissemination to distant sites. The study of BC cell motility will both enable development of anti-invasion therapeutics to limit progression of early-stage disease and improve our understanding of the metastatic process which drives patient mortality in BC. BCs display a great deal of intertumoral heterogeneity, and can be divided into basal and luminal subtypes, which are biologically and clinically distinct entities. Here, I examine the invasion phenotypes of BC as a function of both subtype and epithelial to mesenchymal transition (EMT) status. I studied the impact of Src inhibition on the motility of luminal and basal cell lines. My research demonstrates that while both luminal and basal models exhibit comparable cell signaling phenotypes following exposure to the Src Family Kinase (SFK) inhibitor AZD0530, only luminal models are sensitive to the anti-invasive effects of the compound. I also explore the correlation between the developmental program, EMT, and invasion in a panel of BC cell lines. Models could be broadly categorized as epithelial or mesenchymal, with no significant difference in invasion capacity observed between the two groups. However, the presence of partial EMT did predict invasion within the epithelial clade, with highly epithelial models being substantially less invasive than those exhibiting a hybrid phenotype. The studies detailed here provide rationale for the development of AZD0530 as an anti-invasive agent in BC and evidence for the role of EMT in BC invasion.

Keywords

bladder cancer, Src, AZD0530, tumor invasion, EMT

Available for download on Thursday, April 28, 2022

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