Graduation Date

Winter 12-15-2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Biochemistry & Molecular Biology

First Advisor

Dr. Maneesh Jain

Abstract

This thesis delves into the complexities of pancreatic ductal adenocarcinoma (PDAC) and its microenvironment. This study centers on unraveling the heterogeneity of pancreatic cancer-associated fibroblasts (CAFs) using a panel of patient-derived pancreatic fibroblasts. Additionally, it delves into the realm of G-protein-coupled receptors (GPCRs), with a specific emphasis on the Endothelin receptors (ETAR and ETBR), all within the context of PDAC.

A key achievement is the development of immortalized patient-derived pancreatic fibroblasts (iPDPFs), replicating CAF heterogeneity in PDAC. The iPDPFs were able to recapitulate the PDAC CAF heterogeneity, plasticity, and the overlapping nature of the tumor stroma. Functional characterization of iPDPFs highlighted their roles in ECM remodeling, cancer cell proliferation, and chemoresistance. In vivo studies showed iPDPFs' ability to modify the PDAC microenvironment, affecting drug perfusion and immune cell infiltration.

The research also explored GPCRs in various diseases, revealing their temporal expression patterns and therapeutic potential. Specific GPCR profiles were identified for different CAF subtypes, offering tailored treatment prospects. Within the PDAC microenvironment, the Endothelin Axis (ET-axis), particularly GPCRs ETAR and ETBR, played a multifaceted role, influencing ECM remodeling and promoting pro-tumorigenic functions.

In summary, this thesis enhances our comprehension of CAF heterogeneity using iPDPFs, elucidates GPCR implications in disease contexts, and highlights the ET-axis's significance in the PDAC microenvironment. Future research directions include refining the iPDPF model, validating promising GPCR discoveries, expanding into diverse disease scenarios, and deepening our understanding of the ET-axis. These efforts collectively strive towards the advancement of personalized PDAC treatments.

Comments

2023 Copyright, the authors

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