Tumor-associated fibroblasts derived IBSP promotes gemcitabine resistance in pancreatic cancer by activating the ITGAV-PI3K/Akt pathway.

Pancreatic ductal adenocarcinoma is characterized by an abundant extracellular matrix that contributes significantly to its resistance to chemotherapy. As the predominant cellular component of the tumor stroma, fibroblasts not only establish a physical barrier but also modulate intracellular signaling pathways within tumor cells. In this study, we demonstrate that fibroblasts secrete Integrin Binding Sialoprotein (IBSP) into the extracellular milieu, where it binds to ITGAV on the surface of tumor cells, thereby activating the downstream PI3K/AKT signaling pathway and promoting resistance to gemcitabine-induced apoptosis. Moreover, we confirm that IBSP, as a secreted protein, is stably detectable in peripheral blood and is significantly associated with gemcitabine resistance. Circulating IBSP expression may serve as a potential biomarker for selecting ITGAV inhibitors in combination with gemcitabine to improve chemotherapy responsiveness.