Tumor and stroma COL8A1 secretion induces autocrine and paracrine progression signaling in pancreatic ductal adenocarcinoma

•Enhanced COL8A1 expression was found in PDAC tumor parenchyma and stroma, and in LSL-KrasG12D/+; p48-Cre mice with high-grade pancreatic intraepithelial neoplasia.•Paracrine COL8A1 from cancer associated fibroblasts and autocrine COL8A1 from tumor cells bind to ITGB1 and DDR1 receptors, promoting tumor progression.•COL8A1 expression is elevated by cJun/AP-1 activation in gemcitabine-resistant cancer cells and promotes drug resistance by inducing PI3K/AKT and NF-κB prosurvival signaling.•COL8A1 is a new marker for predicting poor chemotherapy responsiveness and survival in PDAC patients, and serves as a potential therapeutic target.