Date of this Version
Thomas, E. 2023. CXCR1 and Its Role in Cancer Stem Cell-Like Characteristics in Pancreatic Ductal Adenocarcinoma. Undergraduate Honors Thesis. University of Nebraska - Lincoln.
Pancreatic ductal adenocarcinoma (PDAC) has one of the lowest survival rates of all cancers in the United States, in part due to patients presenting with or developing chemotherapy resistance at an elevated frequency. To develop other treatment options, the phenomenon of chemotherapy resistance is being investigated. One area of interest is the sub-population of tumor cells called cancer stem cells (CSCs), which are known for having high resistance to chemotherapy, along with propagating and re-building the tumor after most non-CSCs have been therapeutically targeted. Epithelial-to-mesenchymal transition (EMT) is another mode of chemotherapy resistance of interest, which allows tumor cells to attain a motile mesenchymal phenotype. In the present study, we investigate the inflammatory receptor CXCR1 as a possible marker and therapeutic target for PDAC CSCs. The CXCR1 axis includes the ligands CXCL6 and CXCL8 (IL8), both of which promote the progression of cancer. Previously, Ginesteir et al. (2010) has shown that targeting the CXCR1 axis in triple negative breast cancer reduced CSC-like phenotypes in vitro and in vivo. Investigations of CXCR1 in PDAC have demonstrated that IL8 induces increased tumorsphere formation in vitro (Chen et al., 2014). We hypothesize that PDAC cells with high CXCR1 activity also exhibit increased CSC-like characteristics and undergo EMT, and that targeting CXCR1 will reduce those characteristics. To investigate the role of CXCR1 in chemotherapy-resistant PDAC, we conducted both in vivo and in vitro experiments looking at the expression of CXCR1 and other CSC and EMT markers in both parent cell lines and generated chemotherapy-resistant cell lines. Our results indicate a general increase in marker expression in chemoresistant cells and cells treated with chemotherapy, while treatment with the CXCR1 inhibitor navarixin generally decreases marker expression. This implicates CXCR1 as a potential additional marker for CSCs and EMT in PDAC.