Multidrug resistance (MDR) mediated by MDR1 (ABCB1) P-glycoprotein and related ATP-binding cassette (ABC) transporters is an impediment to successful cancer therapy. ABCB5 P-glycoprotein is a novel ABC transporter, which mediates drug efflux in cancer cells and regulates cell fusion and resultant differentiation of progenitor cells in physiological tissues. It is hypothesized that ABCB5 mediates dual functions in cancer, conferring MDR via its function as a drug efflux transporter, and regulating tumor renewal as a determinant of cell fusion involving tumor stem cells. This study aims to (1) identify systematically ABCB5 drug efflux substrates and examine the role of ABCB5 in the chemoresistance to such compounds, (2) determine whether ABCBS-expressing cancer cells function as tumor stem cells, and (3) investigate the role of ABCB5 in cancer MDR and tumor formation in vivo and examine whether ABCB5 can be specifically targeted for tumor eradication. First, ABCB5 gene and protein expression will be assayed across the NCI-60 cancer cell lines with resistance profiles for >100,000 compounds and drug resistance correlations will be established by. COMPARE analysis. Candidate ABCB5 transport substrates will be validated experimentally using competitive drug efflux analysis in ABCB5 gene-transfected cell lines, and chemosensitivity assays performed in ABCBS-blocked human cancer cell lines and murine ABCB5 -/- knockout cells. Second, the capacity of ABCBS-positive tumor cells vis-a-vis ABCBS-negative tumor bulk populations for self-renewal and the mechanistic contribution of ABCBS-positive progenitor cells to tumor culture growth and differentiation will be examined in vitro using tumor clonogenicity and cell fusion assays. Third, the in vivo role of ABCB5 in chemoresistance to identified drug substrates and the in vivo relevance of ABCBS-positive tumor cells for tumor formation and growth will be studied in human to mouse tumor xenograft models. The results will define the role of ABCB5 in cancer MDR and will establish whether chemoresistant ABCBS- positive cells function as tumor stem cells in expressing cancers. Thus, the findings will identify whether ABCB5 represents a novel therapeutic target in clinical oncology.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-ONC-Q (01))
Program Officer
Forry, Suzanne L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Children's Hospital Boston
United States
Zip Code
Aya-Bonilla, Carlos A; Marsavela, Gabriela; Freeman, James B et al. (2017) Isolation and detection of circulating tumour cells from metastatic melanoma patients using a slanted spiral microfluidic device. Oncotarget :
Kleffel, Sonja; Lee, Nayoung; Lezcano, Cecilia et al. (2016) ABCB5-Targeted Chemoresistance Reversal Inhibits Merkel Cell Carcinoma Growth. J Invest Dermatol 136:838-46
Lutz, Norbert W; Banerjee, Pallavi; Wilson, Brian J et al. (2016) Expression of Cell-Surface Marker ABCB5 Causes Characteristic Modifications of Glucose, Amino Acid and Phospholipid Metabolism in the G3361 Melanoma-Initiating Cell Line. PLoS One 11:e0161803
Schatton, Tobias; Schütte, Ute; Frank, Markus H (2016) Effects of Malignant Melanoma Initiating Cells on T-Cell Activation. Methods Mol Biol :
Jiang, Dongsheng; Muschhammer, Jana; Qi, Yu et al. (2016) Suppression of Neutrophil-Mediated Tissue Damage-A Novel Skill of Mesenchymal Stem Cells. Stem Cells 34:2393-406
Ma, Jie; Frank, Markus H (2015) Isolation of Circulating Melanoma Cells. Methods Mol Biol :
Frank, Markus H; Frank, Natasha Y (2015) Restoring the cornea from limbal stem cells. Regen Med 10:1-4
Gray, Elin S; Reid, Anna L; Bowyer, Samantha et al. (2015) Circulating Melanoma Cell Subpopulations: Their Heterogeneity and Differential Responses to Treatment. J Invest Dermatol 135:2040-2048
de Waard, Nadine E; Kolovou, Paraskevi E; McGuire, Sean P et al. (2015) Expression of Multidrug Resistance Transporter ABCB5 in a Murine Model of Human Conjunctival Melanoma. Ocul Oncol Pathol 1:182-189
Schatton, Tobias; Yang, Jun; Kleffel, Sonja et al. (2015) ABCB5 Identifies Immunoregulatory Dermal Cells. Cell Rep 12:1564-74

Showing the most recent 10 out of 38 publications