The melanoma stem cell can be identified by a few markers such as TIE-1, CD133, nestin and ABCG2. Recently, a novel marker, ABCB5 was identified by Schatton et al. This protein is a transporter protein responsible for the efflux of chemotherapeutic drugs (doxorubicin specifically) from melanoma cells. Schatton et al demonstrated that ABCB5 was expressed in CD133 + cells, and that ABCB5+ cells were capable of self-renewal, and could be serially transplanted in animal xenograft models. ABCB5 was expressed in both primary and metastatic melanomas, and constituted about 2-20% of the tumor cell population. 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, using ABCB5+ as a marker of stemness. We have recently shown that Wnt5A can cause the loss of expression of melanoma differentiation antigens (MDAs), while promoting metastasis. Melanoma stem cells give rise to differentiated tumor cells, and so we are currently exploring the link between ABCB5, MDAs and Wnt5A. We have found thus far that cells which express high levels of MDAs tenc to also express high levels of ABCB5. A very interesting finding is that PCR anlaysis indicates, in our less differentiated, more metastatic melanoma cells, ABCB5 is alternatively spliced. We are currently sequencing this gene to determine if this is due to mutation. If it is, we propose to analyze a series of patient tumors for the ABCB5 mutation, and then perform a functional anlaysis to uncover the significance of this mutation, using both in vitro and in vivo methodology.? Another family of proteins involved in melanoma stem cell development, and melanoma metastasis is the Notch family of proteins. Current data from our laboratory indicates that Wnt5A and Notch proteins may interact to promote wound-healing, and melanoma metastasis. We are exploring this link further, and trying to better understand the interactions between these two families of proteins not just in a cancer setting, but also in the context of normal skin, and skin aging.
| 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 |
| 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 |
| 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 |
