Dr. Frank's laboratory research, conducted in the Transplantation Research Program of Boston Children's Hospital and the Department of Dermatology at Brigham and Women's Hospital, focuses on the physiological and pathological roles of the human P-glycoprotein family of ATP-binding cassette (ABC) transporters. His laboratory has discovered and characterized immunoregulatory functions of the ATP-binding cassette (ABC) transporter ABCB1 (MDR1) P-glycoprotein in alloimmunity. Moreover, his laboratory has cloned and characterized a novel human ABC transporter, ABCB5, which marks mesenchymal stem cell (MSC) subpopulations in human and murine skin. Dr. Frank's work has demonstrated a unique regulatory role of ABCB5 in the newly recognized phenomenon of stem cell fusion, and in cell fusion-dependent growth and differentiation. The identification and characterization of ABCB5 P-glycoprotein as a marker of adult skin-associated stem cells has allowed Dr. Frank's laboratory to initiate studies regarding the differentiation plasticity and immunomodulatory capacity of this unique cell subset in vitro and in vivo. Thus, current and future research efforts of Dr. Frank's laboratory are geared towards using adult skin-derived ABCB5+ stem cells as a transplantable cell source for novel therapeutic applications in tissue engineering and regeneration, and for stem cell-based modulation of transplant allograft rejection and autoimmune disorders.
Dr. Frank's laboratory has also shown that ABCB5 serves as a multidrug resistance transporter in human malignant melanoma, conferring resistance to chemotherapy . Subsequent work has shown that ABCB5 expression 1) marks melanoma cells of stem cell phenotype and function; 2) correlates with tumorigenic growth of melanoma cells in vivo; and 3) is more abundant in human malignant melanoma than in benign melanocytic nevi in human patients (Schatton et al. Nature 2008). Moreover, genetically determined ABCB5 functionality correlates with clinical melanoma risk. Additionally, his laboratory has identified novel T-cell modulatory functions of ABCB5+ melanoma subpopulations that suggest specific roles for these melanoma stem cells in the evasion of antitumor immunity and in cancer immunotherapeutic resistance. Moreover, his laboratory has recently demonstrated that VEGFR-1 function in melanoma stem cells regulates vasculogenic mimicry and the associated stem cell-dependent production of the pro-proliferative melanoma mitogen,laminin, a novel molecular mechanism through which melanoma stem cells promote tumor growth that can be therapeutically targeted in preclinical tumor xenotransplantation models.
Most recently, the Frank laboratory demonstrated that ABCB5 controls IL-1beta secretion in melanoma stem cells, which serves to maintain these slow-cycling, chemoresistant cells through an IL-1beta/IL8/CXCR1 cytokine signaling circuit. This cancer stem cell maintenance circuit involved reciprocal paracrine interactions with ABCB5-negative cancer cell populations. ABCB5 blockade induced cellular differentiation, reversed resistance to multiple chemotherapeutic agents, and impaired tumor growth in vivo. Together, these results defined a novel function for ABCB5 in cancer stem cell maintenance and tumor growth.
In tandem with fundamental approaches to further characterize the functional roles of ABCB5 in normal tissue-specific stem cells and cancer stem cells, Dr. Frank's laboratory explores the clinical relevance of ABCB5 as a biomarker of melanoma progression, prognosis and outcome, and investigates the therapeutic efficacy of ABCB5 targeting in melanoma and additional ABCB5-expressing human malignancies.