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Hypoxia Induces Phenotypic Plasticity and Therapy Resistance in Melanoma via the Tyrosine Kinase Receptors ROR1 and ROR2
Cancer Discovery
  • Michael p O'Connell
  • Katie Marchbank
  • Marie R Webster
  • Alexander A Valiga
  • Amanpreet Kaur
  • Adina Vultur
  • Ling Li
  • Meenhard Herlyn
  • Jessie Villanueva
  • Qin Liu
  • Xiangfan Yin
  • Sandy Widura
  • Janelle Nelson
  • Nivia Ruiz
  • Tura C Camilli
  • Fred E Indig
  • Keith T Flaherty
  • Jennifer A Wargo
  • Dennie T Frederick
  • Zachary A Cooper
  • Suresh G Nair, MD, Lehigh Valley Health Network
  • Ravi K Amaravadi
  • Lynn M Schuchter
  • Giorgos C Karakousis
  • Wei Xu
  • Xiaowei Xu
  • Ashani T Weeraratna
Publication/Presentation Date
12-1-2013
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.

PubMedID
24104062
Document Type
Article
Citation Information

O'Connell, M., Marchbank, K., Webster, M., Valiga, A., Kaur, A., Vultur, A., & ... Weeraratna, A. (2013). Hypoxia Induces Phenotypic Plasticity and Therapy Resistance in Melanoma via the Tyrosine Kinase Receptors ROR1 and ROR2. Cancer Discovery, 3(12), 1378-1393. doi:10.1158/2159-8290.CD-13-0005