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The dense, stiff extracellular matrix, composed primarily of collagen I and basement membrane components such as collagen IV and laminin, acts as a mechanical barrier that constrains PDAC invasion. We investigated whether the actin\u2010related protein (Arp) 2\/3 complex, a key actin nucleator, is essential for PDAC cells to overcome extracellular matrix stiffness and facilitate migration. CRISPR\/Cas9 knockout of the\n                    <jats:italic>Arpc4<\/jats:italic>\n                    gene in murine PDAC cell lines derived from Kras\n                    <jats:sup>G12D<\/jats:sup>\n                    \u2010driven transgenic mice resulted in substantially downregulated all Arp2\/3 complex members. Inactivation of Arp2\/3 significantly impaired PDAC cell migration, disrupted branched tubular structure formation in collagen I, and inhibited invasive front formation in organoid culture together with tumor\u2010associated macrophages and fibroblasts. Mechanistically, \u03b21 integrin signaling emerged as a key regulator of Arp2\/3\u2010dependent migration through collagen\u2010rich matrices. Clinically, elevated expression of Arp2\/3 complex components correlates with poor patient survival and basal\u2010like differentiation subtypes, underscoring its role in disease progression. This study identifies the Arp2\/3 complex and \u03b21 integrin signaling as critical mediators of PDAC invasiveness and suggests them as potential therapeutic targets for mitigating PDAC progression.\n                  <\/jats:p>","DOI":"10.1002\/ijc.70376","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T11:56:25Z","timestamp":1772970985000},"page":"3038-3050","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Arp2\/3 complex and \u03b21 integrin drive an invasive front through extracellular matrix adaptation in pancreatic cancer"],"prefix":"10.1002","volume":"158","author":[{"given":"Xiufen","family":"Yang","sequence":"first","affiliation":[{"name":"Department of General, Visceral and Transplantation Surgery University of Heidelberg  Heidelberg Germany"},{"name":"Department of General and Visceral Surgery Ulm University Hospital  Ulm 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