Hypoxia Induces Phenotypic Plasticity and Therapy Resistance in Melanoma via the Tyrosine Kinase Receptors ROR1 and ROR2

TLDR

Melanoma cells can dynamically switch between a proliferative, poorly invasive state and an invasive, less proliferative state, a process that may drive both metastasis and therapy resistance. The study aims to show that changes in ROR1 and ROR2 expression within the noncanonical Wnt5A pathway direct this phenotype switching and associated drug resistance. The authors find that ROR1 and ROR2 are inversely expressed and mutually repress each other, that hypoxia induces a shift from ROR1⁺ to ROR2⁺ cells with a ten‑fold drop in BRAF‑inhibitor sensitivity, and that Wnt5A levels correlate with clinical resistance, suggesting that targeting the Wnt5A/ROR2 axis could enhance vemurafenib efficacy.

Abstract

An emerging concept in melanoma biology is that of dynamic, adaptive phenotype switching, where cells switch from a highly proliferative, poorly invasive phenotype to a highly invasive, less proliferative one. This switch may hold significant implications not just for metastasis, but also for therapy resistance. We demonstrate that phenotype switching and subsequent resistance can be guided by changes in expression of receptors involved in the noncanonical Wnt5A signaling pathway, ROR1 and ROR2. ROR1 and ROR2 are inversely expressed in melanomas and negatively regulate each other. Furthermore, hypoxia initiates a shift of ROR1-positive melanomas to a more invasive, ROR2-positive phenotype. Notably, this receptor switch induces a 10-fold decrease in sensitivity to BRAF inhibitors. In patients with melanoma treated with the BRAF inhibitor vemurafenib, Wnt5A expression correlates with clinical response and therapy resistance. These data highlight the fact that mechanisms that guide metastatic progression may be linked to those that mediate therapy resistance.These data show for the fi rst time that a single signaling pathway, the Wnt signaling pathway, can effectively guide the phenotypic plasticity of tumor cells, when primed to do so by a hypoxic microenvironment. Importantly, this increased Wnt5A signaling can give rise to a subpopulation of highly invasive cells that are intrinsically less sensitive to novel therapies for melanoma, and targeting the Wnt5A/ROR2 axis could improve the efficacy and duration of response for patients with melanoma on vemurafenib.