Kolarzyk, Anna M. Kwon, Yujin Oh, Elizabeth Lee, Keng-Jung Cho, Su-Yeon Cano, Issahy Lu, Renhao Kwak, Tae Joon Lee, Jaehyun Wong, Gigi Kim, Andrew H. Gandarilla, Omar Hidalgo, Manuel Kim, Won Kyu Lee, Esak 2025-07-30T06:00:21Z 2025-07-30T06:00:21Z 2025-07-28 2025-07 1476-4598 https://pubs.kist.re.kr/handle/201004/152889 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 (TGF beta) receptors have been extensively studied in many cancer types. However, activin receptor-like kinase 7 (ALK7), one of the TGF beta 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-beta-catenin-EMT axis enhances intrinsic tumor cell motility, driving epithelial-mesenchymal transition (EMT). In parallel, the ALK7-beta-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. English BioMed Central Non-canonical ALK7 pathways promote pancreatic cancer metastasis through β-catenin/MMP-mediated basement membrane breakdown and intravasation Article 10.1186/s12943-025-02384-w 1 Molecular Cancer, v.24, no.1 Molecular Cancer 24 1 Y scie scopus 001522719700001 2-s2.0-105010081120 Biochemistry & Molecular Biology Oncology Biochemistry & Molecular Biology Oncology Article TGF-BETA INVADOPODIA EXPRESSION OVEREXPRESSION SURVIVAL BARRIER ROLES CELLS MMP-7 GENE ALK7 Matrix metalloproteinases Organ-on-a-chip Intravasation Pancreatic cancer