DKK3 Initially Preserves Acinar Integrity Through MEK‐Fos Signaling, but Later Switches to an Oncogenic Role in Pancreatic Cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by its intricate biology governed by spatiotemporal dynamics in the expression and function of specific proteins. Here, DKK3 is identified as a dynamic player with a dual role in PDAC. Using the KRAS ^G12D ‐driven mouse model with homozygous (DDKC) and heterozygous (DKC) DKK3 knockout, its stage and compartment‐specific functions are investigated. Knockout mice exhibited shorter lifespans with a higher incidence of high‐grade, desmoplastic, and metastatic cancers. DKK3‐deficient acini exhibited a marked increase in acinar‐to‐ductal metaplasia, with increased MAPK signaling and induction of the downstream effector Fos . During the progression of mouse and human PDAC, DKK3 expression shifted from epithelial dysplastic cells to cancer‐associated fibroblasts (CAFs). At the endpoint, DKK3‐expressing CAFs emerged as crucial contributors to tumor aggressiveness and fibrosis. Orthotopic transplantations confirm a stromal role, particularly in DDKC tumors, while mechanistic studies demonstrate that DKK3 activates IL6‐JAK‐STAT3 signaling and pro‐migratory/mesenchymal programs that are reversed by pharmacologic STAT3 inhibition in DDKC cells. Concordantly, DKK3 expression correlates with IL6‐JAK‐STAT3 gene signatures in human PDAC datasets. Together, these findings underscore the intricate and context‐sensitive role of DKK3, delaying oncogenesis during early stages while paradoxically promoting tumor progression in later stages, suggesting that therapeutic targeting strategies should be approached with caution.