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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, The Wistar Institute
  • Katie Marchbank, The Wistar Institute
  • Marie R Webster, The Wistar Institute
  • Alexander A Valiga, The Wistar Institute
  • Amanpreet Kaur, The Wistar Institute
  • Adina Vultur, The Wistar Institute
  • Ling Li, The Wistar Institute
  • Meenhard Herlyn, The Wistar Institute
  • Jessie Villanueva, The Wistar Institute
  • Qin Liu, The Wistar Institute
  • Xiangfan Yin, The Wistar Institute
  • Sandy Widura, The Wistar Institute
  • Janelle Nelson, The Wistar Institute
  • Nivia Ruiz, The Wistar Institute
  • Tura C Camilli, The National Institute on Aging
  • Fred E Indig, The National Institute on Aging
  • Keith T Flaherty, Dana-Farber/Harvard Cancer Center
  • Jennifer A Wargo, Dana-Farber/Harvard Cancer Center
  • Dennie T Frederick, Dana-Farber/Harvard Cancer Center
  • Zachary A Cooper, Dana-Farber/Harvard Cancer Center
  • Suresh G Nair, MD, Lehigh Valley Health Network
  • Ravi K Amaravadi, University of Pennsylvania
  • Lynn M Schuchter, University of Pennsylvania
  • Giorgos C Karakousis, University of Pennsylvania
  • Wei Xu, University of Pennsylvania
  • Xiaowei Xu, University of Pennsylvania
  • Ashani T Weeraratna, The Wistar Institute
Publication/Presentation Date
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.
Document Type
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