Frequent loss of adhesion gene NECTIN1 triggers melanoma dissemination upon local IGF1 depletion [RNA-Seq]

Defects in cell-cell contacts participate in early steps of tumor metastasis, but the mechanism regulating the staying-at-home or leaving decision has not been molecularly defined. We found the adherens junction gene NECTIN1 deleted in 55% of human melanomas. Inactivation of NECTIN1 stimulated cancer cell spreading in zebrafish melanomas in vivo, and increased cell migration in human cell lines specifically in response to decreased IGF1 signaling. IGF1 inhibition induced robust formation of adherens junctions between NECTIN1-wildtype melanoma cells, while NECTIN1-deficient cells were unable to establish these junctions and instead activated integrin/FAK-mediated motility. In 20 human melanoma biopsies, adherens junctions were seen exclusively in areas with low IGF1 levels, but not in NECTIN1-deficient tumors. Our study uncovers a mechanism by which the status of cell-cell contacts modulates the cellular response to microenvironmental signals, effecting a decision switch between leaving and staying in the cancer cell niche. Overall design: In order to define the cell state associated with the loss of NECTIN1 under conditions of serum depletion, we examined the transcriptional profiles of A375 human melanoma cells wildtype or knockout for NECTIN1 in response to serum withdrawal by RNA-sequencing. We analyzed gene expression in 4 NECTIN1-wildtype and 4 NECTIN1-knockout lines derived from the A375 human melanoma cell line by single-cell cloning and cultured in DMEM in the absence of 10% FBS for 12 hours.