BioProject

Purpose: Herein we demonstrate that UV-induced melanomas of low metastatic potential in mice that overexpress HGF and harbor deletion of the Ink4a/p16 locus (HP strain) are converted to highly metastatic forms by virtue of hemizygous deletion of the metastasis suppressor genes Nme1 and Nme2 (HPN strain). More...

Purpose: Herein we demonstrate that UV-induced melanomas of low metastatic potential in mice that overexpress HGF and harbor deletion of the Ink4a/p16 locus (HP strain) are converted to highly metastatic forms by virtue of hemizygous deletion of the metastasis suppressor genes Nme1 and Nme2 (HPN strain). The striking difference in metastatic activity between HP and HPN melanomas strains provided a powerful system for identifying molecular profiles associated with metastatic activity. Methods: Primary and metastatic melanoma RNAseq profiling. Results: RNA-seq analysis of primary melanomas identified a 32-gene expression signature that was strongly associated with the HPN genotype and lung metastatic activity (HPN lung metastasis signature, or HPN-LMS). Expression of the HPN-LMS was highly predictive of overall survival in human cohorts of cutaneous melanoma (SKCM) and uveal melanoma (UVM) patients of The Cancer Genome Atlas (TCGA). Conclusions: Three HPN-LMS genes (ARRDC3, NYNRIN, RND3) associated with longer survival in SKCM and/or UVM patients exhibited strong anti-invasion activity in human melanoma cells, consistent with roles as effectors of the metastasis suppressor functions of Nme1 and Nme2. The HP/HPN mouse paradigm has thus yielded a network of potential therapeutic targets and prognostic markers for clinical management of metastatic melanoma. Overall design: RNAseq of primary and metastatic melanomas in Nme1+/- / Nme2+/- mouse strain. Less...