RACK1 cooperates with NRASQ61K to promote melanoma in vivo

Melanoma is the deadliest skin cancer. RACK1 (Receptor for activated protein kinase C) protein was proposed as a biological marker of melanoma in human and domestic animal species harboring spontaneous melanomas. As a scaffold protein, RACK1 is able to coordinate the interaction of key signaling molecules implicated in both physiological cellular functions and tumorigenesis. A role for RACK1 in rewiring ERK and JNK signaling pathways in melanoma cell lines had been proposed. Here, we used a genetic approach to test this hypothesis in vivo in the mouse. We show that Rack1 knock-down in the mouse melanoma cell line B16 reduces invasiveness and induces cell differentiation. We have developed the first mouse model for RACK1 gain of function, Tyr::Rack1-HA transgenic mice, targeting RACK1 to melanocytes in vivo. RACK1 overexpression was not sufficient to initiate melanomas despite activated ERK and AKT. However, in a context of melanoma predisposition, RACK1 overexpression reduced latency and increased incidence and metastatic rate. In primary melanoma cells from Tyr::Rack1-HA, Tyr::NRasQ61K mice, activated JNK (c-Jun N-terminal kinase) and activated STAT3 (signal transducer and activator of transcription 3) acted as RACK1 oncogenic partners in tumoral progression. A sequential and coordinated activation of ERK, JNK and STAT3 with RACK1 is shown to accelerate aggressive melanoma development in vivo.Fil: Campagne, C.. Institut National de la Recherche Agronomique; Francia. Ecole Nationale Vétérinaire d'Alfort; Francia. Université Paris-Est; FranciaFil: Reyes-Gomez, E.. Institut National de la Recherche Agronomique; Francia. Ecole Nationale Vétérinaire d'Alfort; Francia. Université Paris-Est; FranciaFil: Picco, María Elisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Loiodice, S.. Institut National de la Recherche Agronomique; Francia. Ecole Nationale Vétérinaire d'Alfort; Francia. Université Paris-Est; FranciaFil: Salaun, P.. Institut National de la Recherche Agronomique; Francia. Ecole Nationale Vétérinaire d'Alfort; Francia. Université Paris-Est; FranciaFil: Ezagal, J.. Institut National de la Recherche Agronomique; Francia. Ecole Nationale Vétérinaire d'Alfort; Francia. Université Paris-Est; FranciaFil: Bernex, F.. Institut National de la Recherche Agronomique; Francia. Ecole Nationale Vétérinaire d'Alfort; Francia. Université Paris-Est; FranciaFil: Commère, P. H.. Instituto Pasteur; FranciaFil: Pons, S.. Instituto Pasteur; FranciaFil: Esquerre, D.. Institut National de la Recherche Agronomique; Francia. Universite Toulose 1 Capitole; FranciaFil: Bourneuf, E.. Institut National de la Recherche Agronomique; Francia. Université Paris-Saclay; FranciaFil: Estellé, J.. Institut National de la Recherche Agronomique; Francia. Université Paris-Saclay; FranciaFil: Maskos, U.. Instituto Pasteur; Francia. Centre National de la Recherche Scientifique; FranciaFil: Lopez Bergami, Pablo Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico; ArgentinaFil: Aubin Houzelstein, G.. Institut National de la Recherche Agronomique; Francia. Ecole Nationale Vétérinaire d'Alfort; Francia. Université Paris-Est; FranciaFil: Panthier, J.J.. Institut National de la Recherche Agronomique; Francia. Instituto Pasteur; Francia. Université Paris-Est; FranciaFil: Egidy, G.. Institut National de la Recherche Agronomique; Francia. Université Paris-Saclay; Francia. Université Paris-Est; Franci