Role of the ROR2 receptor in the progression of melanoma

Orphan receptor tyrosine kinase 2 (ROR2) is a receptor for the Wnt5a ligand that is aberrantly expressed in cancer and that suppresses or promotes tumor progression depending on the tumor type. In the present work we describe that ROR2 is a critical regulator of “phenotypic switch”, a process with great similarities with the epithelial mesenchymal transition (EMT) involved in melanoma progression.
We describe here that ROR2 inhibits the PI3K/Akt pathway and modulates the expression of main cell cycle regulators, decreasing the expression of CDK4, PCNA, Cyclin D1, A, and B, and the phosphorylation of RB, favoring its nuclear localization, and increasing the expression of Cyclin E and the inhibitory phosphorylation of CDK1. These changes affect cell cycle progression, reduce proliferation and inhibit tumor growth in vivo. Along these lines, ROR2 expression in primary melanomas is negatively correlated with AJCC stage, mitotic rate, degree of ulceration, and Breslow thickness. In addition, ROR2 correlates with a higher overall survival, indicating that ROR2 is a marker of good prognosis in primary melanoma.
In contrast, ROR2 promotes cell migration and an increase in the expression of EMT markers such as Vimentin, N-Cadherin, Snail, ZEB1, among others. Studies in xenotransplanted mice demonstrated that ROR2 also promoted EMT, invasion, and necrosis in vivo. Consistent with the induction of “phenotypic switch”, ROR2 promotes an increase in resistance to various cytotoxic compounds. The increase in chemoresistance is the result of an increase in the levels of the anti-apoptotic proteins Mcl-1 and Bcl-xL, a decrease in the pro-apoptotic proteins Bax and Bid, and an increase in MDM2 with the consequent downregulation of p53. Both EMT induction and increased chemoresistance are mediated by phosphorylation and activation of ERK.
Finally, we observed that ROR2 levels increase in samples of metastasis and that high levels of ROR2 in lymph nodes correlate with lower overall survival and distant metastasis. Altogether, these results demonstrate that ROR2 is a regulator of phenotypic plasticity in melanoma by inhibiting proliferation and promoting EMT and chemoresistance. In summary, our results identify ROR2 as a driver of “phenotypic change” and a promising therapeutic target to block melanoma metastasis.