Abstract

We have shown that Wnt5A is a molecule that is important in the progression of melanoma cells to a highly metastatic state. Recently we have demonstrated that Wnt5A acts via the orphan tyrosine kinase receptor, ROR2, and that this interaction is modulated by heparan sulfate proteoglycans such as syndecan 4. The signaling of Wnt5A involves changes in the cytoskeleton, activation of an epithelial to mesenchymal transition and the loss of immunogenicity via the downregulation of melanocyte differentiation antigens and pigment. These features are consistent with a de-differentiation phenotype of melanoma cells. Given recent data that suggested that the Wnt protein, Wnt5A, can affect the proliferation and maintenance of hemaopoietic stem cells, we are trying to determine what the role, if any, of Wnt5A in the maintenance and profileration of the melanoma stem cell might be, and how this relates to the role of Wnt5A in melanoma metastasis.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000450-02
Application #
7963979
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2009
Total Cost
$251,405
Indirect Cost

  Institution

Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code

  Publications

Camilli, Tura C; Weeraratna, Ashani T (2010) Striking the target in Wnt-y conditions: intervening in Wnt signaling during cancer progression. Biochem Pharmacol 80:702-11
O'Connell, M P; Fiori, J L; Xu, M et al. (2010) The orphan tyrosine kinase receptor, ROR2, mediates Wnt5A signaling in metastatic melanoma. Oncogene 29:34-44
Fiori, Jennifer L; Zhu, Tie-Nian; O'Connell, Michael P et al. (2009) Filamin A modulates kinase activation and intracellular trafficking of epidermal growth factor receptors in human melanoma cells. Endocrinology 150:2551-60
Pinnix, Chelsea C; Lee, John T; Liu, Zhao-Jun et al. (2009) Active Notch1 confers a transformed phenotype to primary human melanocytes. Cancer Res 69:5312-20
O'Connell, Michael P; Fiori, Jennifer L; Baugher, Katherine M et al. (2009) Wnt5A activates the calpain-mediated cleavage of filamin A. J Invest Dermatol 129:1782-9
O'Connell, Michael P; Weeraratna, Ashani T (2009) Hear the Wnt Ror: how melanoma cells adjust to changes in Wnt. Pigment Cell Melanoma Res 22:724-39
Buac, Kristina; Xu, Mai; Cronin, Julie et al. (2009) NRG1 / ERBB3 signaling in melanocyte development and melanoma: inhibition of differentiation and promotion of proliferation. Pigment Cell Melanoma Res 22:773-84
Ghosh, Manik C; Collins, Gary D; Vandanmagsar, Bolormaa et al. (2009) Activation of Wnt5A signaling is required for CXC chemokine ligand 12-mediated T-cell migration. Blood 114:1366-73
Schwartz, Anthony L; Malgor, Ramiro; Dickerson, Eric et al. (2009) Phenylmethimazole decreases Toll-like receptor 3 and noncanonical Wnt5a expression in pancreatic cancer and melanoma together with tumor cell growth and migration. Clin Cancer Res 15:4114-22
O'Connell, Michael P; Fiori, Jennifer L; Kershner, Emily K et al. (2009) Heparan sulfate proteoglycan modulation of Wnt5A signal transduction in metastatic melanoma cells. J Biol Chem 284:28704-12

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