The tumor cell‐secreted matricellular protein WISP 1 drives pro‐metastatic collagen linearization

Abstract

Collagen linearization is a hallmark of aggressive tumors and a key pathogenic event that promotes cancer cell invasion and metastasis. Cell‐generated mechanical tension has been proposed to contribute to collagen linearization in tumors, but it is unknown whether other mechanisms play prominent roles in this process. Here, we show that the secretome of cancer cells is by itself able to induce collagen linearization independently of cell‐generated mechanical forces. Among the tumor cell‐secreted factors, we find a key role in this process for the matricellular protein WISP1 (CCN4). Specifically, WISP1 directly binds to type I collagen to promote its linearization in vitro (in the absence of cells) and in vivo in tumors. Consequently, WISP1‐induced type I collagen linearization facilitates tumor cell invasion and promotes spontaneous breast cancer metastasis, without significantly affecting gene expression. Furthermore, higher WISP1 expression in tumors from cancer patients correlates with faster progression to metastatic disease and poor prognosis. Altogether, these findings reveal a conceptually novel mechanism whereby pro‐metastatic collagen linearization critically depends on a cancer cell‐secreted factor.

Concepts of extracellular matrix remodelling in tumour progression and metastasis

“…The force-mediated fibronectin assembly creates anisotropic fibre orientation and can open gaps in the matrix that allow cell migration 175 . Collagen linearization can also be mediated by tumour-secreted factors such as the WNT1 inducible signalling pathway gene (WISP1) 176 , which is triggered by TGF-β.…”

Reciprocal Interplay Between Fibrillar Collagens and Collagen-Binding Integrins: Implications in Cancer Progression and Metastasis

“…The aligned collagen fibers provide tracks not only for cancer cells but also for macrophages, thereby promoting their migration into the TME (124). Recently, WISP1, a matricellular protein secreted by cancer cells, was shown to induce collagen linearization by binding directly type I collagen, thereby promoting its linearization, independently of cell-derived mechanical tensions (125). Moreover, fibroblast activation protein (FAP), another important ECM-associated proteinase, promotes the formation in vitro of desmoplastic-like aligned matrices (126) and its overexpression has been associated with a poor patient outcome.…”

The Matrix Revolution: Matricellular Proteins and Restructuring of the Cancer Microenvironment

“…The POSTN family member MGP was recently shown to be incorporated into crosslinked multimers of fibronectin, which enhanced cancer cell attachment to fibronectin (23). As for the CCN family, recent studies have shown CCN1, CCN2 and CCN4 to promote alignment and stability of collagen fibers (13,157,176…”