Graduation Date

Spring 5-4-2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pathology & Microbiology

First Advisor

Rakesh K. Singh, Ph.D.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, the fourth leading cause of cancer-related deaths in the USA with over 40,000 deaths per year. Unlike other major cancer types, the progress in dealing with PDAC is plodding, attributed mainly to the asymptomatic nature of the disease, the late diagnosis and the ineffectiveness of current therapies. A better understanding of the biology of the disease could permit the discovery of novel diagnostic and therapeutic tools. With that in mind, we present this dissertation that investigates the tumor-stromal interaction underlined by genetic alterations and inflammation. PDAC develop as a consequence of the accumulation of genetic mutations like Kras. Oncogenic Kras is known to propagate inflammatory signals such as CXCR2. PDAC is known for the prominent desmoplasia that enables therapy resistance and tumor dissemination, which is mainly mediated through cancer-associated fibroblasts (CAFs). Little is known about the connection between oncogenic Kras, CXCR2 signaling and CAFs. In this study, we show that CAFs can produce CXCR2 ligands and can respond to CXCR2 signaling. We indicated that through paracrine factors such as CXCL8 and FGF-2, CAFs support the survival of the aggressive PDAC cells and enable means for progression. We demonstrate that oncogenic Kras is associated with a subset of CAFs with a prominent secretory function mediated through CXCR2 signaling. Lastly, we exhibit a differential role of CXCR2 in PDAC that was dependent on genetic mutations, which may indicate a temporal context of CXCR2 roles in PDAC. Together, CAFs, as well as CXCR2, could still be worthy targets in PDAC in the III right context. Further studies that investigate the progression and timely roles of CAFs and CXCR2 are warranted.

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