Minor Type IV Collagen α5 Chain Promotes Cancer Progression through Discoidin Domain Receptor-1

Type IV collagens (Col IV), components of basement membrane, are essential in the maintenance of tissue integrity and proper function. Alteration of Col IV is related to developmental defects and diseases, including cancer. Col IV a chains form alpha 1 alpha 1 alpha 2, alpha 3 alpha 4 alpha 5 and alpha 5 alpha 5 alpha 6 protomers that further form collagen networks. Despite knowledge on the functions of major Col IV (alpha 1 alpha 1 alpha 2), little is known whether minor Col IV (alpha 3 alpha 4 alpha 5 and alpha 5 alpha 5 alpha 6) plays a role in cancer. It also remains to be elucidated whether major and minor Col IV are functionally redundant. We show that minor Col IV alpha 5 chain is indispensable in cancer development by using alpha 5(IV)-deficient mouse model. Ablation of alpha 5(IV) significantly impeded the development of Kras(G12D)-driven lung cancer without affecting major Col IV expression. Epithelial alpha 5(IV) supports cancer cell proliferation, while endothelial alpha 5(IV) is essential for efficient tumor angiogenesis. alpha 5(IV), but not alpha 1(IV), ablation impaired expression of non-integrin collagen receptor discoidin domain receptor-1 (DDR1) and downstream ERK activation in lung cancer cells and endothelial cells. Knockdown of DDR1 in lung cancer cells and endothelial cells phenocopied the cells deficient of alpha 5(IV). Constitutively active DDR1 or MEK1 rescued the defects of alpha 5(IV)-ablated cells. Thus, minor Col IV alpha 5(IV) chain supports lung cancer progression via DDR1-mediated cancer cell autonomous and non-autonomous mechanisms. Minor Col IV can not be functionally compensated by abundant major Col IV.