TY - JOUR
T1 - Hypoxia induces phenotypic plasticity and therapy resistance in melanoma via the tyrosine kinase receptors ROR1 and ROR2
AU - O'Connell, Michael P.
AU - Marchbank, Katie
AU - Webster, Marie R.
AU - Valiga, Alexander A.
AU - Kaur, Amanpreet
AU - Vultur, Adina
AU - Li, Ling
AU - Herlyn, Meenhard
AU - Villanueva, Jessie
AU - Liu, Qin
AU - Yin, Xiangfan
AU - Widura, Sandy
AU - Nelson, Janelle
AU - Ruiz, Nivia
AU - Camilli, Tura C.
AU - Indig, Fred E.
AU - Flaherty, Keith T.
AU - Wargo, Jennifer A.
AU - Frederick, Dennie T.
AU - Cooper, Zachary A.
AU - Nair, Suresh
AU - Amaravadi, Ravi K.
AU - Schuchter, Lynn M.
AU - Karakousis, Giorgos C.
AU - Xu, Wei
AU - Xu, Xiaowei
AU - Weeraratna, Ashani T.
PY - 2013/12
Y1 - 2013/12
N2 - 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. SIGNIFICANCE: These data show for the first 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.
AB - 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. SIGNIFICANCE: These data show for the first 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.
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U2 - 10.1158/2159-8290.CD-13-0005
DO - 10.1158/2159-8290.CD-13-0005
M3 - Article
C2 - 24104062
AN - SCOPUS:84890063283
SN - 2159-8274
VL - 3
SP - 1378
EP - 1393
JO - Cancer discovery
JF - Cancer discovery
IS - 12
ER -