Abstract
The mean survival of metastatic melanoma is less than 1 year. While the high mortality rate is associated with the efficient metastatic colonization of the involved organs, the underlying mechanisms remain elusive. The role of exosomes in facilitating the interactions between cancer cells and the metastatic microenvironment has received increasing attention. Previous studies on the role of exosomes in metastasis have been heavily focused on cancer cell-derived exosomes in modulating the functions of stromal cells. Whether the extravasated neighboring cancer cells at the distant organ can alter the metastatic properties of one another, a new mechanism of metastatic colonization, has not been demonstrated prior to this report. In this study, a paired M4 melanoma derivative cell lines, i.e., M14-OL and POL, that we established and characterized were employed. They exhibit high (POL cells) and low (OL cells) metastatic colonization efficiency in vivo, respectively. We show that exosomal crosstalk between metastatic cancer cells is a new mechanism that underlies cancer metastasis and heterogeneity. Low metastatic melanoma cells (OL) can acquire the "metastatic power" from highly metastatic melanoma cells (POL). POL achieves this goal by utilizing its exosomes to deliver functional miRNAs, such as miR-199a-1-5p, to the targeted OL cell which in turn inactivates cell cycle inhibitor CDKN1B and augments metastatic colonization.