Proinvasion Metastasis Drivers in Early-Stage Melanoma Are Oncogenes

SummaryClinical and genomic evidence suggests that the metastatic potential of a primary tumor may be dictated by prometastatic events that have additional oncogenic capability. To test this “deterministic” hypothesis, we adopted a comparative oncogenomics-guided function-based strategy involving: (1) comparison of global transcriptomes of two genetically engineered mouse models with contrasting metastatic potential, (2) genomic and transcriptomic profiles of human melanoma, (3) functional genetic screen for enhancers of cell invasion, and (4) evidence of expression selection in human melanoma tissues. This integrated effort identified six genes that are potently proinvasive and oncogenic. Furthermore, we show that one such gene, ACP5, confers spontaneous metastasis in vivo, engages a key pathway governing metastasis, and is prognostic in human primary melanomas.

► Integrates melanoma mouse models and human genomics data to derive cancer gene list ► Uses a function-based screening approach to identify oncogenic metastasis drivers ► Shows that ACP5 engages the FAK-signaling complex and is prognostic in melanoma ► Metastatic events present in early tumors can reflect their oncogenic capability