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Semaphorins, specifically type IV, are important regulators of axonal guidance and have been increasingly implicated in poor prognoses in a number of different solid cancers. In conjunction with their cognate PLXNB family receptors, type IV members have been increasingly shown to mediate oncogenic functions necessary for tumor development and malignant spread. In this study, we investigated the role of semaphorin 4C (SEMA4C) in osteosarcoma growth, progression, and metastasis. We investigated the expression and localization of SEMA4C in primary osteosarcoma patient tissues and its tumorigenic functions in these malignancies. We demonstrate that overexpression of SEMA4C promotes properties of cellular transformation, while RNAi knockdown of SEMA4C promotes adhesion and reduces cellular proliferation, colony formation, migration, wound healing, tumor growth, and lung metastasis. These phenotypic changes were accompanied by reductions in activated AKT signaling, G1 cell cycle delay, and decreases in expression of mesenchymal marker genes SNAI1, SNAI2, and TWIST1. Lastly, monoclonal antibody blockade of SEMA4C in vitro mirrored that of the genetic studies. Together, our results indicate a multi-dimensional oncogenic role for SEMA4C in metastatic osteosarcoma and more importantly that SEMA4C has actionable clinical potential.

Numerous studies have demonstrated the importance of altered hyaluronan metabolism to malignant progression of multiple tumor types, including breast carcinomas. Increased hyaluronan (HA) metabolism in the stroma of primary tumors promotes activation of oncogenic signaling pathways that impact tumor initiation, growth, and invasion. Carcinoma cell synthesis and assembly of HA-rich pericellular matrices induces a stromal-independent phenotype, which is associated with cancer progression. Although the pro-tumorigenic role of stromal HA is well established, a novel but unexplored hypothesis is that carcinoma cell-associated HA pericellular matrices promote metastasis of circulating tumor cells. Here, we report the development of an in vitro assay that employs microfluidic techniques to directly measure the importance of an HA-rich pericellular matrix in the entry of carcinoma cells into ectopic sites. This model provides the capability to visualize specific steps in metastasis, which is difficult using animal models. The results show that the presence of a HA-rich pericellular matrix correlates to the invasive and metastatic potential of breast carcinoma cells. Furthermore, enzymatic removal or pharmacologic inhibition of HA synthesis significantly inhibits carcinoma cell extravasation and invasion in this model system. These results implicate pericellular HA-rich carcinoma cell associated pericellular matrices in colonization of ectopic sites by circulating tumor cells and support specific targeting of this matrix to limit metastasis in patients.