Abstract 243: ABCB5 is functionally required for melanoma growth.

Melanoma remains a disease with relatively few beneficial treatments currently available, for late-stage patients. The ATP-binding cassette (ABC) transporter ABCB5 has recently been identified as a cell-surface marker for malignant melanoma initiating cells (MMICs; Schatton et al, Nature 2008), opening a new paradigm for investigation of this aggressive cancer. We have previously demonstrated that these ABCB5+ MMICs can evade the host immune system, and also express VEGFR-1, required for efficient tumor formation. However, the possibility that ABCB5 itself plays a functional role in melanoma tumorigenic growth and progression has not been investigated, until now. To test whether ABCB5 plays a functional role in melanoma growth, or is solely a marker of the cancer stem-cell subset, we generated ABCB5-shRNA knockdown (ABCB5-KD) cell populations in melanoma model cell-lines. To distinguish a bona fide role in intrinsic tumorigenesis from immuno-modulatory effects we subcutaneously injected these cells, versus control cells, into highly immunocompromised NOD/SCID Il2rγ-/- mice and followed tumor progression. We observed a marked and significant downregulation in the ability of ABCB5-KD cells to maintain efficient tumor growth, implying a direct role for ABCB5 in melanoma progression. To obtain mechanistic data to explain this phenotype we generated RNA from ABCB5-KD cells versus controls, and performed microarray analysis of global genomic changes in transcript levels of these cells. We then validated potential “ABCB5-pathway” genes, which also change in the reciprocal manner in an ABCB5 overexpression system that we have developed. Our study links ABCB5 to a direct role in melanoma carcinogenesis, identifies genes and pathways of interest, and uncovers ABCB5 as a putative master-regulator of melanoma. Citation Format: Brian J. Wilson, Karim R. Saab, Tobias Schatton, Jie Ma, George F. Murphy, Martin Gasser, Ana Maria Waaga-Gasser, Natasha Y. Frank, Markus H. Frank. ABCB5 is functionally required for melanoma growth. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 243. doi:10.1158/1538-7445.AM2013-243