COL4A2 drives ECM remodeling and stiffness increasing to promote breast cancer metastasis via YAP signaling pathway in dECM induced models

Mechanical stress significantly increases during tumor progression. Accumulated research focuses on mechanical transduction, due to the great therapeutic difficulties brought by the mechanical changes. Extracellular matrix (ECM) serves as the key tissue microenvironment providing mechanical cues for tumor cells. However, the mechanism of tumor ECM assembly, stiffness and the resulting cellular mechanical response were rarely reported. Here, decellularized ECM (dECM) models from low-metastatic and metastatic breast cancer tissues via in situ tumor implantation of mammary fat pad in immunodeficient mice were generated to simulate the tumor microenvironment. Wavy fiber structure, finer fibers, but higher stiffness were revealed in the metastatic dECM. Elevated expression of type IV collagen (COL IV) was correlated with the enhanced cell migration and the higher ECM stiffness due to the increased crosslinking of collagen fibers. Further analysis identified COL4A2 (a subunit of COLIV) as a key protein involved in this process. Virus infection of tumor cells led to a decrease in COL4A2 specificity in the dECM in situ, accompanied by the decreased ECM stiffness, the inhibition of cell migration in vitro, and the reduction of metastasis in vivo. Additionally, the increased ECM stiffness caused by the high content of COL4A2 in dECM scaffolds activated YAP1 expression, which might be a potential mechanism. Therefore, the promotion of the stiffness in the basement membrane by COL4A2 via collagen fiber cross-linking might be a key mechanical target for breast cancer metastasis. The targeting ECM mechanics could offer a new strategy to inhibit tumor progression.