RACK1 cooperates with NRAS to promote melanoma in vivo

Abstract

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::NRas 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.

Rack1 mediates tyrosine phosphorylation of Anxa2 by Src and promotes invasion and metastasis in drug-resistant breast cancer cells

“…Rack1 inhibits the invasion ability of colon cancer cells [33]. Moreover, Rack1 negatively regulates the invasiveness and metastasis of cancer cells in gastric cancer [32,34]; On the contrary, Rack1 promotes invasion and metastasis of prostate cancer and hepatocellular carcinoma cells [61,62]; Consistently, knockdown of Rack1 reduces invasion in melanoma, oral squamous carcinoma cells, and lung cancer cells [35,36,38,63]. In this study, silencing Rack1 in drug-resistant cells inhibited invasion ability in vitro and metastasis potential in vivo.…”

“…Consistently, Anxa2 associates with STAT3 and confers the aggressive behavior in colorectal cancer [46,66]. Interestingly, Rack1 is also involved in the activation of STAT3 in several cancer cells [36,67]. Src is also a well-known upstream kinase of STAT3, and enhanced STAT3 activation confers invasiveness of drug-resistant breast cancer cells [8].…”

“…Except for colon and gastric cancer [32][33][34], Rack1 appears to play a tumor-promoting role in other carcinomas [29][30][31]. Additionally, Rack1 overexpression has been correlated to proliferation, invasion, and metastasis [35][36][37][38]. In particular, higher Rack1 level is an independent predictor for poor prognosis in breast cancer.…”

The MeLiM Minipig: An Original Spontaneous Model to Explore Cutaneous Melanoma Genetic Basis

“…Later, this scaffold protein with multiple functions has been described as a good marker for differentiating melanocytoma from melanoma in dog ( Campagne et al, 2013 ) and horse ( Campagne et al, 2012 ). More recently, Campagne et al (2017) showed that RACK1 could cooperate with NRAS Q61K mutation to accelerate melanoma onset and metastasis formation in transgenic mice. This example illustrates the usefulness of such a model to describe the role of pivotal molecules in specific pathologies.…”

Classification and Grading of Melanocytic Lesions in a Mouse Model of NRAS-driven Melanomagenesis

“…Following these initial observations, the Tg(Tyr-NRAS*Q61K)1Bee background has quickly become a reference genetic system where to explore in vivo candidate gene function, investigate the role of cooperating mutations, validate biomarkers, and test therapeutic strategies. 11–16…”