RASSF1C oncogene elicits amoeboid invasion, cancer stemness, and extracellular vesicle release via a SRC/Rho axis:prev. Amoeboid cells are stem-like and induce non-cell autonomous metastasis in vivo

Activation of the GTPase RhoA increases actinomyosin contractility and a population of highly invasive amoeboid-like cells in tumours. Here we identified that the pro-metastatic oncogene RASSF1C is an activator of RhoA/ROCK signaling and amoeboid motility in cells with stem cell-like attributes. RhoA-driven amoeboid cell movement also induces the release of extracellular vesicles that promote non-cell autonomous migration and metastasis in recipient cells. Mechanistically, RASSF1C localises in the uropod like structure of fast A2-amoeboid motile cells where it activates pMLCII and supports contractility required for forward movement. In addition, amoeboid cells secret integrin-rich extracellular vesicles that support uropod attachment which are released in to the milieu upon initiation of movement. The higher level of amoeboid cells in RASSF1C+/RhoA+ tumours results in elevated A2 motility, an associated increase in vesicle release and promotion of metastasis in benign tumour cells in vivo, unravelling a common mechanism behind diverse phenotypic attributes of cancer cells.