The study of cell motility and plasticity in cancer: the role of the crosstalk between BM-MSCs and tumor in osteosarcoma progression and Claisened Hexafluoro as potential inhibitor of amoeboid motility in metastatic melanoma

Part 1 Growing evidence suggest that bone marrow-derived mesenchymal stem cells (BM-MSCs) are key players in tumor stroma. Here, we investigated the cross-talk between BM-MSCs and osteosarcoma (OS) cells in tumor progression. We revealed a strong tropism of BM-MSCs towards these tumor cells and identified monocyte chemoattractant protein (MCP)-1, growth-regulated oncogene (GRO)-α and transforming growth factor (TGF)-β1 as pivotal factors for BM-MSC chemotaxis. Once in contact with OS cells, BM-MSCs trans-differentiate into cancer-associated fibroblasts, further increasing MCP-1, GRO-α, interleukin (IL)-6 and IL-8 levels in the tumor microenvironment. These cytokines promote mesenchymal to amoeboid transition (MAT), driven by activation of the small GTPase RhoA, in OS cells, as illustrated by the in vitro assay and live imaging. The outcome is a significant increase of aggressiveness in OS cells in terms of motility, invasiveness and trans-endothelial migration. In keeping with their enhanced trans-endothelial migration abilities, OS cells stimulated by BM-MSCs also sustain migration and invasion. Thus, BM-MSC recruitment to the OS site and the consequent cytokine-induced MAT are crucial events in OS malignancy. Part 2 Metastatic melanoma is one of the most aggressive and lethal malignancies with a poor prognosis. Melanoma cells are able to migrate using different types of cell motility such as the rounded/amoeboid-type motility and the elongated/mesenchymal-type motility thanks to their high plasticity. Really several data underline the crucial role of amoeboid motility in the dissemination process of highly metastatic melanoma cells. Thus, targeting this process could be a promising strategy to prevent the metastatic spreading of melanoma cells. Claisened Hexafluoro is a chemical analog of Honokiol (HKL), a biphenolic compound derived from Magnolia officinalis which has antitumoral and antimetastatic effect in numerous cancers, including melanoma. Starting from these evidence, here we tested Claisened Hexafluoro on human metastatic melanoma cells, as an inhibitor of amoeboid motility. Data here reported demonstrate that Claisened Hexafluoro, impairing mitochondrial activity and affecting AMP-activated protein kinase (AMPK) signaling, strongly inhibits amoeboid motility and many steps of the disseminating process in vitro as well as in vivo, confirming its possible future application to fight metastatic spreading of melanoma cells.