The matricellular protein WISP2 is an endogenous inhibitor of collagen linearization and cancer metastasis

Collagen linearization leads to cancer metastasis and poor prognosis but there are no therapies to target it. In addition to cell-generated mechanical forces, collagen linearization is triggered by the interaction of collagen with WISP1 (CCN4), a TGFb1-induced factor secreted by cancer cells. However, it remains unknown how WISP1 is physiologically regulated and whether it could be targeted to prevent collagen linearization. Here, we show that WISP2 (CCN5), a secreted factor downregulated in tumors, is an endogenous inhibitor of type I collagen (Col I) linearization. Mechanistically, WISP2 prevents WISP1 binding to Col I, thereby inhibiting WISP1-induced Col I linearization. Consequently, restoration of WISP2 via overexpression in tumor cells or via treatments with recombinant WISP2 impairs WISP1-induced or TGFb1-induced cancer cell invasion and spontaneous metastasis in vivo. Overall, this study uncovers WISP2 as an endogenous competitive inhibitor of WISP1 and reveals that collagen linearization is controlled by secreted factors with antagonistic functions. Overall design: Here 3 samples of 4T1 cells, a murine breast cancer cell line, were transformed such that WISP2 was over expressed. These samples wrre compared to 4T1 controls transformed with an empty vector: GSM3018746, GSM3018748, and GSM3018749 in other analyses not presented here.