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Nevertheless, mutated <jats:italic>KRAS<\/jats:italic> alone is insufficient to initiate pancreatic intraepithelial neoplasia (PanIN), the precursor of PDAC. The identities of the other factors\/events required to drive PanIN formation remain elusive. Here, optic\u2010clear 3D histology is used to analyze entire pancreases of 2\u2010week\u2010old <jats:italic>Pdx1<\/jats:italic>\u2010<jats:italic>Cre<\/jats:italic>; <jats:italic>LSL<\/jats:italic>\u2010<jats:italic>Kras<\/jats:italic><jats:sup>G12D\/+<\/jats:sup> (KC) mice to detect the earliest emergence of PanIN and observed that the occurrence is independent of physical location. Instead, it is found that the earliest PanINs overexpress Muc4 and associate with \u03b1SMA<jats:sup>+<\/jats:sup> fibroblasts in both transgenic mice and human specimens. Mechanistically, <jats:italic>Kras<\/jats:italic><jats:sup>G12D\/+<\/jats:sup> pancreatic cells upregulate Muc4 through genetic alterations to increase proliferation and fibroblast recruitments via Activin A secretion and consequently enhance cell transformation for PanIN formation. Inhibition of Activin A signaling using Follistatin (FST) diminishes early PanIN\u2010associated fibroblast recruitment, effectively curtailing PanIN initiation and growth in KC mice. These findings emphasize the vital role of interactions between oncogenic <jats:italic>Kras<\/jats:italic><jats:sup>G12D\/+<\/jats:sup>\u2010driven genetic alterations and induced microenvironmental changes in PanIN initiation, suggesting potential avenues for early PDAC diagnostic and management approaches.<\/jats:p>","DOI":"10.1002\/advs.202301240","type":"journal-article","created":{"date-parts":[[2023,11,15]],"date-time":"2023-11-15T15:17:49Z","timestamp":1700061469000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Oncogenic KRAS, Mucin 4, and Activin A\u2010Mediated Fibroblast Activation Cooperate for PanIN Initiation"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4248-0896","authenticated-orcid":false,"given":"Chun\u2010Mei","family":"Hu","sequence":"first","affiliation":[{"name":"Genomics Research Center Academia Sinica  Taipei 11529 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