Date of Award

2022

Embargo Period

6-27-2027

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biochemistry and Molecular Biology

College

College of Graduate Studies

First Advisor

Michael C. Ostrowski

Second Advisor

John P. O'Bryan

Third Advisor

Denis Guttridge

Fourth Advisor

Robin Muise-Helmericks

Fifth Advisor

Chrystal M. Paulos

Abstract

Pancreatic Ductal Adenocarcinoma (PDAC) is associated with a desmoplastic stroma that can contribute to its recalcitrance to therapy. Cancer-associated fibroblasts (CAFs) are one of the most abundant cell types within the PDAC stroma; yet, their contribution to PDAC growth and development remain unclear. Targeting CAFs to improve PDAC therapeutic treatment is thought to be an incredibly promising strategy, however; studies have shown both tumor-promoting and tumor-limiting activities associated with PDAC CAFs. Therefore, understanding specific tumor-promoting pathways in CAFs is essential for developing better stromal targeting therapies. STAT3 is a transcription factor activates both cell survival and proliferation programs as well as immune modulating cytokines and chemokines. In PDAC, STAT3 is often aberrantly expressed and known to be a tumor driver within the epithelium, however, its stromal specific function in PDAC has yet to be elucidated. We hypothesized that STAT3 signaling in pancreatic CAFs contributes to the immunosuppressive and fibrotic stroma observed with disease progression. Using two different mouse models of PDAC, we investigate how loss of STAT3 in CAFs influences tumor growth and the tumor microenvironment (TME). Deletion of STAT3 in CAFs not only slows tumor progression and increases survival, but re-shapes the characteristic immunosuppressive TME by decreasing M2 macrophages and increasing CD8+ T cells. Mechanistically, we show that loss of the tumor suppressor PTEN in pancreatic CAFs leads to an increase in STAT3 phosphorylation. Additionally, increased STAT3 phosphorylation in pancreatic CAFs promotes secretion of CXCL1. Inhibition of CXCL1 signaling inhibits M2 polarization in vitro. The results in this thesis provide direct genetic evidence for the role of STAT3 in CAFs in promoting tumor progression and an immunosuppressive TME, and a potential mechanism by which CAFs regulate these activities.

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