Oncogenic effects of activated RAS at the GC. a Expression of the indicated constructs transfected (1 μg) in CHL melanocytes. b Kaplan–Meier plot of the Incidence of melanoma by 10 weeks post fertilization in nacre zebrafish expressing the indicated HRASV12 site-specific transgenes using the miniCoopR system. c Representative images of adult zebrafish expressing the indicated HRASV12 site-specific transgenes at 8 weeks post fertilization compared to nacre. Insets are magnification of stripes. d Representative images of zebrafish embryos expressing the indicated HRASV12 site-specific transgenes at 3 days post fertilization compared to uninjected nacre. e Apoptosis induction by the indicated HRASV12 site-specific constructs in CHL melanoma cells. Results, relative to the values found in vector-transfected cells, show average ± SEM from three independent experiments **p < 0.01 by Student's t-test. See also Supplementary Fig. 7

PTPRκ is a tumor suppressor in melanoma. a Analysis of PTPRκ expression in normal skin (n = 7), benign nevi (n = 18) and cutaneous melanoma samples (n = 45) generated using an available gene dataset, accessed through the Oncomine® platform. ***p < 0.001 ****p < 0.0001 by Student's t-test. b Survival curves for melanoma patients depending on PTPRκ expression levels (obtained from GEO GSE65904). c View of naevi (2/28; arrowhead, middle panel) and melanoma (2/28; arrowhead bottom panel, points to a protruding eye with a retroorbital tumor.) by 52 weeks post fertilization in ptprκ nullizygous zebrafish expressing KDELr-HV12 as a transgene. Representative pictures were taken at 8 weeks post fertilization. d Kaplan–Meier plot of tumor development in ptprκ wild-type nacre animals compared to ptprk−/− nacre animals, injected with NRAS-G12D. ****p < 0.0001 by Mantel-Cox test. e Representative melanoma lesions (see arrowheads) in zebrafish with the indicated ptprκ genotype expressing NRAS-G12D as a transgene. See also Supplementary Fig. 8

TP53 status determines GC RAS-induced melanomagenesis. a Analysis of PTPRκ and TP53 mutational status generated using the TCGA dataset accessed through the cBioPortal for Cancer Genomics platform. b Survival curves for melanoma patients depending on PTPRκ expression levels and tp53 mutational status (obtained from TCGA melanoma dataset). c Effects of TP53 inactivation on ERK phosphorylation and apoptosis induced by GC RAS signals, as revealed in MCF-7 cells transfected with the indicated constructs. Data show average ± SEM from three independent experiments. ***p < 0.005 by Student's t-test. d Effects of TP53 status on ERK phosphorylation and apoptosis induced by GC RAS signals, as revealed in MEFs, wild-type (wt) and tp53-null,transfected with KDELr-HV12 (1 μg) where shown (+). Data show average ± SEM from three independent experiments. ***p < 0.005 by Student's t-test. e tp53 inactivation is sufficient to promote melanomagenesis by GC RAS signals. Arrowheads show melanoma lesions in tp53−/− zebrafish expressing the KDEL-HV12 transgene after 14 weeks. See also Supplementary Fig. 9

Macroscopic view of representative fish expressing the indicated HRASV12 site-­‐specific transgenes after 14 weeks.

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