Author ORCID Identifier

0000-0003-0010-6625

Date of Graduation

5-2022

Document Type

Dissertation (PhD)

Program Affiliation

Biochemistry and Molecular Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Mary C. Farach-Carson

Committee Member

Daniel Carson

Committee Member

Zhiqiang An

Committee Member

Andrew Gladden

Committee Member

John Putkey

Abstract

The extracellular matrix (ECM) is a complex, interconnected network of three major constituents: collagens, glycoproteins, and proteoglycans, along with their enzyme modifiers. Within this network and beyond the structural role, each ECM molecule contributes a context-specific signal that influences cellular fate and behavior. Among these behaviors, cellular migration provides an essential function in developing tissues, wound healing, and cancer cell metastasis. Using two glandular organs, the normal salivary gland and the cancerous prostate, this dissertation describes the tissue-specific composition of two ECM signaling complexes (type I hemidesmosomes and the perlecan-semaphorin 3A-plexin A1-neuropilin-1 (PSPN) complex) and translates this knowledge into viable solutions for both tissue engineering and cancer metastasis applications. Database (Matrisome/FANTOM5) and two-dimensional and three-dimensional cell culture analysis identified collagen XVII and the heparan sulfate proteoglycan perlecan/HSPG2 as two key ECM components controlling cell cohesion and migration in salivary gland and prostate cancer (PCa) epithelial cells, respectively. These two matrix proteins maintain key roles in the induction of migratory signaling events through their respective signaling complexes. In the first study, using combined biochemical and unbiased computational approaches, we identified key signatures promoter-level gene expression of 274 core ECM proteins in a tissue-specific manner. In the second study, collagen XVII in type I hemidesmosomes was studied in the context of migration and complex microstructure organization of salivary stem/progenitor cells in salivary morphogenesis. In the third study, perlecan, in the newly identified PSPN complex, was found to control the cohesion-dyscohesion axis of PCa tumoroids, indicative of its role in controlling PCa metastasis. Taken together, the discoveries from this work can be leveraged to create new treatment options that control cell behavior for those patients with damaged glands experiencing xerostomia/dry mouth and in need of salivary gland restoration or patients with PCa metastases.

Keywords

ECM, prostate cancer, salivary, migration

Available for download on Thursday, October 27, 2022

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