EXOSOMES DERIVED FROM METASTATIC COLON CANCER CELLS TRANSFER MALIGNANT PHENOTYPIC TRAITS TO SURROUNDING CELLS: THEIR EMERGING ROLE IN TUMOR HETEROGENEITY

Abstract

Several studies have clearly demonstrated that within a heterogeneous tumor mass the inter-clonal cooperation between metastatic and non-metastatic cells can facilitate the tumor progression. Recent accumulating evidence has highlighted that tumor-derived exosomes (TDEs) play a relevant role as mediator of the inter-clonal collaborative cooperation affecting the properties of both tumor and non-tumor component. In this context, our goal was to understand if exosomes derived from highly metastatic cells may influence the behaviour of less aggressive tumor cells and the properties of endothelium. We found that metastatic SW620 cells transfer through exosomes (SW620Exos) their round/amoeboid phenotype to elongated non-metastatic SW480 cells also inducing the increase of the motile and invasive activities. Moreover, SW620Exos caused endothelial hyperpermeability by altering the junctional complexes in HUVECs. The SWATH-based quantitative proteomic analysis highlighted that SW620Exos were significant enriched in several proteins related to the RhoA/ROCK sig¬naling, known to induce the amoeboid motility as well as the destabilization of endothelial junctional complexes. According to this data, we found that the treatment with ExoSW620 elicited in both SW480 cells and HUVECs the increase of RhoA activity, while the induced morphological and functional effects were reverted by co-treatment with a specific ROCK inhibitor. RacGap1 and thrombin were identified as putative key mediators of the effects induced by SW620Exos in target cells. Taken together our data indicates that within a heterogeneous tumor mass exosomes released by metastatic cells affect the features of both tumor and non-tumor cell components, thus contributing to accelerate the metastatic cascade.