Comprehensive molecular profiling of UV-induced metastatic melanoma in Nme1/Nme2-deficient mice reveals novel markers of survival in human patients

• Published in: Oncogene Vol. 40; no. 45; pp. 6329 - 6342
• Main Authors: Leonard, M. Kathryn, Puts, Gemma S., Pamidimukkala, Nidhi, Adhikary, Gautam, Xu, Yili, Kwok, Eric, Jin, Yuxin, Snyder, Devin, Matsangos, Nicolette, Novak, Marián, Mahurkar, Anup, Shetty, Amol C., Slominski, Radomir M., De Fabo, Edward C., Noonan, Frances P., Day, Chi-Ping, Rigi, Mohammed, Slominski, Andrzej T., Webb, Michelle G., Craig, David W., Merlino, Glenn, Eckert, Richard L., Carpten, John D., Manojlovic, Zarko, Kaetzel, David M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.11.2021; Nature Publishing Group
• Subjects: 38/1; 38/109; 38/22; 38/23; 38/39; 38/44; 38/77; 38/89; 38/90; 38/91; 42/40; 42/41; 42/44; 631/208/69; 631/67/1813/1634; 64/110; 82/29; 82/80; 96/106; Animals; Apoptosis; Biomarkers, Tumor - genetics; BRCA1 protein; Cell Biology; Development and progression; Diagnosis; Gene deletion; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genetic aspects; Genetic markers; Genomes; Health aspects; Hepatocyte growth factor; Hepatocyte Growth Factor - genetics; Human Genetics; Humans; Identification and classification; INK4 protein; Internal Medicine; Invasiveness; Lung Neoplasms - genetics; Lung Neoplasms - secondary; Lungs; Medicine; Medicine & Public Health; Melanoma; Melanoma - etiology; Melanoma - genetics; Metastases; Metastasis; Mice; Missense mutation; Mutation, Missense; NM23 Nucleoside Diphosphate Kinases - genetics; Oncology; Patients; Prognosis; Sequence Analysis, RNA; Survival Analysis; Therapeutic targets; Transcriptomes; Tumors; Ultraviolet radiation; Ultraviolet Rays - adverse effects; Whole Genome Sequencing; United States
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-021-01998-w

Hepatocyte growth factor-overexpressing mice that harbor a deletion of the Ink4a / p16 locus (HP mice) form melanomas with low metastatic potential in response to UV irradiation. Here we report that these tumors become highly metastatic following hemizygous deletion of the Nme1 and Nme2 metastasis suppressor genes (HPN mice). Whole-genome sequencing of melanomas from HPN mice revealed a striking increase in lung metastatic activity that is associated with missense mutations in eight signature genes ( Arhgap35 , Atp8b4 , Brca1 , Ift172 , Kif21b , Nckap5 , Pcdha2, and Zfp869 ). RNA-seq analysis of transcriptomes from HP and HPN primary melanomas identified a 32-gene signature (HPN lung metastasis signature) for which decreased expression is strongly associated with lung metastatic potential. Analysis of transcriptome data from The Cancer Genome Atlas revealed expression profiles of these genes that predict improved survival of patients with cutaneous or uveal melanoma. Silencing of three representative HPN lung metastasis signature genes ( ARRDC3 , NYNRIN , RND3 ) in human melanoma cells resulted in increased invasive activity, consistent with roles for these genes as mediators of the metastasis suppressor function of NME1 and NME2 . In conclusion, our studies have identified a family of genes that mediate suppression of melanoma lung metastasis, and which may serve as prognostic markers and/or therapeutic targets for clinical management of metastatic melanoma.