Abstract
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 α chains form α1α1α2, α3α4α5 and α5α5α6 protomers that further form collagen networks. Despite knowledge on the functions of major Col IV (α1α1α2), little is known whether minor Col IV (α3α4α5 and α5α5α6) 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 α5 chain is indispensable in cancer development by using α5(IV)-deficient mouse model. Ablation of α5(IV) significantly impeded the development of KrasG12D-driven lung cancer without affecting major Col IV expression. Epithelial α5(IV) supports cancer cell proliferation, while endothelial α5(IV) is essential for efficient tumor angiogenesis. α5(IV), but not α1(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 α5(IV). Constitutively active DDR1 or MEK1 rescued the defects of α5(IV)-ablated cells. Thus, minor Col IV α5(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.
Highlights
Basement membranes (BMs), specialized extracellular matrices separating epithelial and endothelial cells from underlying mesenchyme, provide cells with structural support, as well as morphogenic and functional cues [1,2,3]
Multiple trimers are formed by highly homologous α chains for certain types of collagens (e.g. α1α1α2, α3α4α5 and α5α5α6 heterotrimers for type IV collagen)
Type IV collagens are named as major type (α1α1α2) or minor type (α3α4α5 and α5α5α6), mainly reflecting the abundance and tissue distribution, but not the importance of their biological functions
Summary
Basement membranes (BMs), specialized extracellular matrices separating epithelial and endothelial cells from underlying mesenchyme, provide cells with structural support, as well as morphogenic and functional cues [1,2,3]. Type IV collagens (Col IV) are major components of BMs [1,3]. Col IV-initiated signals are essential survival and growth cues for liver metastasis in diverse tumor types [6]. BM proteins, including α1(IV), protect small cell lung cancer cells from chemotherapy-induced apoptosis [8]. Blood vessel formation and survival are connected with proper collagen synthesis and deposition in BMs. Col IV, by binding to cell surface receptors, activates intracellular signaling events to promote cell survival, proliferation and tumorigenesis [5]. Β1 integrin and its downstream effecter focal adhesion kinase (FAK) are critical in mediating resistance to anoikis, chemotherapy-induced cell death and metastasis [6,8,11] Loss of integrin α1β1 ameliorates KrasG12D-induced lung cancer [11,12]. β1 integrin and its downstream effecter focal adhesion kinase (FAK) are critical in mediating resistance to anoikis, chemotherapy-induced cell death and metastasis [6,8,11]
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