The CXCR1 as a putative marker for cancer stem cell-like phenotypes in chemotherapy-resistant pancreatic ductal adenocarcinoma

Cancer stem cells (CSCs) are a rare but critical subpopulation in pancreatic ductal adenocarcinoma (PDAC), contributing to therapy resistance and disease relapse. The CXCR1 signaling axis has been implicated in CSC maintenance across multiple cancers. We investigated the role of CXCR1 in CSC-like phenotypes in PDAC by analyzing its expression, along with established CSC markers, in chemotherapy-resistant (GemR) and parental PDAC cell lines under various treatment conditions. GemR cells exhibited elevated levels of CXCR1, its ligand CXCL6, and CSC markers compared to parental lines. Gemcitabine treatment increased the expression of CXCR1 and CSC-associated markers in parental cells, suggesting therapy-induced enrichment of CSC-like populations. Additionally, GemR cells had a higher frequency of CD44⁺/CXCR1⁺ cells. In parental cells, gemcitabine also induced markers of epithelial-to-mesenchymal transition (EMT), a phenotype associated with CSC plasticity. Combination treatment with gemcitabine and Navarixin, a CXCR1 inhibitor, significantly reduced expression of CXCR1, CXCL6, and CSC/EMT markers in vitro. <i>In vivo</i>, tumors treated with the combination therapy showed markedly lower CXCR1 and CXCL6 expression than other treatment groups. These findings indicate that the CXCR1 axis supports CSC maintenance in PDAC, and that co-targeting CSC and non-CSC populations may improve therapeutic outcomes.