Date of Award

2017

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Pharmacology

First Advisor

Ellen Pur�

Abstract

Heterogeneous activated fibroblasts that deposit and remodel extracellular matrix (ECM) comprise desmoplasia, a key regulator of tumor development. The divergent outcomes in response to varied therapies targeting intratumoral desmoplasia underscore the pressing need to delineate the intricate role of a heterogeneous stroma in tumorigenesis. Fibroblast activation protein (FAP) and alpha-smooth muscle actin (αSMA) identify distinct, yet overlapping, activated fibroblast subsets in myriad tumor types, fibrosis, and wound healing. FAPHi reactive fibroblasts and αSMAHi myofibroblasts can exert divergent influences on tumor progression. However, the factors that drive this phenotypic heterogeneity and the unique functional roles of these distinct phenotypes are not yet understood. By comparing fibroblast activation on fibronectin- and collagen I-coated hydrogels of varying stiffness, I demonstrated that a convergence of ECM composition, elasticity, and TGF-β signaling governs activated fibroblast phenotypic heterogeneity. Furthermore, by characterizing gene expression signatures, I revealed potentially unique roles of activated fibroblast subsets in tissue remodeling.

In addition to its utility as a marker of activated fibroblasts, FAP also constitutes a highly attractive drug target due to its selective expression in the tumor microenvironment and its pro-tumorigenic proteolytic activity. FAP-mediated proteolysis of collagen I and III fragments promotes collagen clearance. However, the potential mechanistic link between FAP’s role in collagen proteolysis and tumorigenesis is not yet known. I investigated the role of FAP-dependent collagen proteolysis and ECM remodeling in tumorigenesis using both a spontaneous oncogenic Kras-driven lung tumor model and fibroblast-derived matrices. I found that Fap genetic deletion promotes intratumoral fibrillar collagen accumulation and attenuates lung tumor multiplicity, size, progression, and proliferation. Furthermore, I obtained preliminary evidence that Fap-/- lung fibroblasts produce ECM with enhanced fibrillar collagen accumulation, which directly impedes both tumor cell proliferation and motility. Taken together, my research underscores the essential role of ECM remodeling in regulating key aspects of tumorigenesis, such as intratumoral fibroblast heterogeneity, proliferation, and invasion.

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