Non-canonical ALK7 pathways promote pancreatic cancer metastasis through β-catenin/MMP-mediated basement membrane breakdown and intravasation.

Breaching the vascular barrier is a critical step in pancreatic ductal adenocarcinoma (PDAC) metastasis, yet the mechanisms enabling this process remain incompletely understood. Transforming growth factor beta (TGFβ) receptors have been extensively studied in many cancer types. However, activin receptor-like kinase 7 (ALK7), one of the TGFβ receptors, is under-investigated, and its roles in PDAC metastasis have been unclear. This study identifies two distinct but interconnected ALK7-driven non-canonical pathways that promote PDAC dissemination. The ALK7-β-catenin-EMT axis enhances intrinsic tumor cell motility, driving epithelial-mesenchymal transition (EMT). In parallel, the ALK7-β-catenin-MMP axis facilitates metastatic invasion by upregulating MMP production, leading to ECM degradation and invadosome formation, which promote vascular barrier breakdown and intravasation. An orthotopic PDAC metastasis model reveals that both pharmacological and genetic ALK7 inhibition suppresses metastasis. 3D microfluidic vessel-on-chip platforms further demonstrate that ALK7 inhibition preserves basement membrane (BM) integrity, limiting intravasation. While MMP inhibition effectively blocks BM breakdown and intravasation, extravasation remains unaffected, highlighting distinct molecular requirements for different metastatic stages. These findings establish ALK7 as a dual-function pro-metastatic regulator that orchestrates both tumor cell plasticity and ECM remodeling, positioning ALK7 inhibition as a promising strategy to target early metastatic dissemination in PDAC.