In conclusion, we show here for the first time that OPN promotes the EMT and CSC‐like properties of PCCs by activating the integrin αvβ3‐Akt/Erk‐FOXM1 cascade in a paracrine manner, suggesting that targeting the tumor microenvironment represents a promising therapeutic strategy in pancreatic cancer. Here, SPP1 is linked to familial pancreatic carcinoma.