Significance Pancreatic ductal adenocarcinoma is one of the most malignant human tumors for which there are no efficacious therapeutic strategies. This tumor type is characterized by an abundant desmoplastic stroma that promotes tumor progression. Yet recent studies have shown that physical or genetic elimination of the stroma leads to more aggressive tumor development. Here, we decided to reprogram the stromal tissue by identifying and subsequently targeting genes responsible for their protumorigenic properties. Comparative transcriptome analysis revealed several genes overexpressed in cancer-associated fibroblasts compared with those present in normal pancreata. We provide genetic evidence that one of these genes, Saa3 , plays a key role on the protumorigenic properties of the stroma, opening the door to the design of future therapeutic strategies.