Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies, due to its aggressive invasiveness and resistance to therapy. 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-related 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 Arpc4 gene in murine PDAC cell lines derived from KrasG12D-driven 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-associated macrophages and fibroblasts. Mechanistically, β1 integrin signaling emerged as a key regulator of Arp2/3-dependent migration through collagen-rich matrices. Clinically, elevated expression of Arp2/3 complex components correlates with poor patient survival and basal-like differentiation subtypes, underscoring its role in disease progression. This study identifies the Arp2/3 complex and β1 integrin signaling as critical mediators of PDAC invasiveness and suggests them as potential therapeutic targets for mitigating PDAC progression.
Yang et al. (Sat,) studied this question.