Doctor of Philosophy (PhD)
Immunology, Pathology & Infectious Disease
Rakesh K. Singh
gemcitabine, cytokines, drug resistance, neoplasm, carcinoma, pancreatic ductal, pancreatic neoplasm, neoplastic processes, chemokines, neoplastic stem cells
Pancreatic ductal adenocarcinoma (PDAC) is notoriously challenging to diagnose and treat. This tumor has an aggressive phenotype and benign clinical features until severe disease dissemination, which makes it too late to eradicate. Although it is only the 10th most common cancer in the United States, it is the fourth leading cause of cancer-related deaths. The treatment options are complicated further due to tumor heterogeneity, meaning not all tumor cells are in the same state phenotypically or epigenetically. They also express cytokines, chemokines, and receptors differently. Here we explore the usage of CXCR1 and CXCR2 and their ligands in PDAC tumor progression and chemoresistance. These two axes are G-protein-coupled receptors with many downstream effectors. Historically known for their role in neutrophil activation and recruitment, the literature discerns that many tumors also utilize them for angiogenesis, survival, proliferation, and migration. In this dissertation research, we investigated these receptors and their ligands in three studies. First, we evaluated their role in PDAC growth and metastasis through in vivo modeling with CXCR1/2 antagonist treatment. We demonstrate that CXCR1/2 antagonism decreases proliferation and increases apoptosis; higher necrosis associated with II higher fibrosis. We then demonstrated that CXCR2 and its ligands CXCL1, 5, and 8 have increased expression in the gemcitabine-resistant derived cell lines. Only parental cell lines have increased CXCR2 axis expression in the presence of gemcitabine, which is concentration- and dose-dependent. The CXCR1/2 antagonists decrease cell proliferation alone and in combination with gemcitabine in the parental- and gemcitabine-resistant cell lines. In vivo studies of the CD18/HPAF gemcitabine-resistant cell line support that combination treatment is superior for these tumors. Our final study evaluated CXCR1 as potential cancer stem cell marker and therapeutic target. The results exhibit a strong association between cancer stem cell markers and CXCR1, with combination treatment decreasing the percentage of cancer stem cell marker-expressing cells. Together, CXCR1 and CXCR2 prove to be therapeutic targets in PDAC, allowing us to target several tumor phenotypes. These results lay strong groundwork for the continued exploration of these receptors as a therapeutic option to eliminate PDAC.
Molczyk, Caitlin, "Targeting the CXCR1/2 Axis in Pancreatic Ductal Adenocarcinoma" (2023). Theses & Dissertations. 722.
Available for download on Saturday, February 22, 2025