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Here, DKK3 is identified as a dynamic player with a dual role in PDAC. Using the KRAS\n                    <jats:sup>G12D<\/jats:sup>\n                    \u2010driven mouse model with homozygous (DDKC) and heterozygous (DKC) DKK3 knockout, its stage and compartment\u2010specific functions are investigated. Knockout mice exhibited shorter lifespans with a higher incidence of high\u2010grade, desmoplastic, and metastatic cancers. DKK3\u2010deficient acini exhibited a marked increase in acinar\u2010to\u2010ductal metaplasia, with increased MAPK signaling and induction of the downstream effector\n                    <jats:italic>Fos<\/jats:italic>\n                    . During the progression of mouse and human PDAC, DKK3 expression shifted from epithelial dysplastic cells to cancer\u2010associated fibroblasts (CAFs). At the endpoint, DKK3\u2010expressing 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\u2010JAK\u2010STAT3 signaling and pro\u2010migratory\/mesenchymal programs that are reversed by pharmacologic STAT3 inhibition in DDKC cells. Concordantly,\n                    <jats:italic>DKK3<\/jats:italic>\n                    expression correlates with IL6\u2010JAK\u2010STAT3 gene signatures in human PDAC datasets. Together, these findings underscore the intricate and context\u2010sensitive 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.\n                  <\/jats:p>","DOI":"10.1002\/advs.202417606","type":"journal-article","created":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T14:40:54Z","timestamp":1761662454000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["DKK3 Initially Preserves Acinar Integrity Through MEK\u2010Fos Signaling, but Later Switches to an Oncogenic Role in Pancreatic Cancer"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-7968-9240","authenticated-orcid":false,"given":"Dharini","family":"Srinivasan","sequence":"first","affiliation":[{"name":"Institute for Molecular Oncology and Stem Cell Biology Ulm 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