Matricellular Protein WISP2 Is an Endogenous Inhibitor of Collagen Linearization and Cancer Metastasis.

Collagen remodeling contributes to many physiologic and pathologic processes. In primary tumors, the linearization of collagen fibers promotes cancer cell invasion and metastasis and is indicative of poor prognosis. However, it remains unknown whether there are endogenous inhibitors of collagen linearization that could be exploited therapeutically. Here, we show that collagen linearization is controlled by two secreted matricellular proteins with antagonistic functions. Specifically, WISP1 was secreted by cancer cells, bound to type I collagen (Col I), and linearized Col I via its cysteine-rich C-terminal (CT) domain. In contrast, WISP2, which lacks a CT domain, inhibited Col I linearization by preventing WISP1-Col I binding. Analysis of patient data revealed that WISP2 expression is lower in most solid tumors, in comparison with normal tissues. Consequently, genetic or pharmacologic restoration of higher WISP2 levels impaired collagen linearization and prevented tumor cell invasion and metastasis in vivo in models of human and murine breast cancer. Thus, this study uncovers WISP2 as the first inhibitor of collagen linearization ever identified and reveals that collagen architecture can be normalized and metastasis inhibited by therapeutically restoring a high WISP2:WISP1 ratio. SIGNIFICANCE: Two secreted factors, WISP1 and WISP2, antagonistically regulate collagen linearization, and therapeutically increasing the WISP2:WISP1 ratio in tumors limits collagen linearization and inhibits metastasis.See related commentary by Barcus and Longmore, p. 5611.

Correlated Evolution of Acrobatic Display and Both Neural and Somatic Phenotypic Traits in Manakins (Pipridae).

Brightly colored manakin (Aves: Pipridae) males are known for performing acrobatic displays punctuated by non-vocal sounds (sonations) in order to attract dull colored females. The complexity of the display sequence and assortment of display elements involved (e.g., sonations, acrobatic maneuvers, and cooperative performances) varies considerably across manakin species. Species-specific display elements coevolve with display-distinct specializations of the neuroanatomical, muscular, endocrine, cardiovascular, and skeletal systems in the handful of species studied. Conducting a broader comparative study, we previously found positive associations between display complexity and both brain mass and body mass across eight manakin genera, indicating selection for neural and somatic expansion to accommodate display elaboration. Whether this gross morphological variation is due to overall brain and body mass expansion (concerted evolution) versus size increases in only functionally relevant brain regions and growth of particular body ("somatic") features (mosaic evolution) remains to be explored. Here, we test the hypothesis that cross-species variation in male brain mass and body mass is driven by mosaic evolution. We predicted positive associations between display complexity and variation in the volume of the cerebellum and sensorimotor arcopallium, brain regions which have roles in sensorimotor processes, and learning and performance of precisely timed and sequenced thoughts and movements, respectively. In contrast, we predicted no associations between the volume of a limbic arcopallial nucleus or a visual thalamic nucleus and display complexity as these regions have no-specific functional relationship to display behavior. For somatic features, we predicted that the relationship between body mass and complexity would not include contributions of tarsus length based on a recent study suggesting selection on tarsus length is less labile than body mass. We tested our hypotheses in males from 12 manakin species and a closely related flycatcher. Our analyses support mosaic evolution of neural and somatic features functionally relevant to display and indicate that sexual selection for acrobatic complexity increases the capacity for procedural learning via cerebellar enlargement and may decrease maneuverability via increases in tarsus length.

The tumor cell-secreted matricellular protein WISP1 drives pro-metastatic collagen linearization.

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.