DF/HCC Program Affiliation

Member, Cutaneous Oncology and Melanoma Program

Research Abstract

Dr. Frank’s laboratory research focuses on the physiological and pathological roles of the human P-glycoprotein family of ATP-binding cassette (ABC) transporters. His laboratory has cloned and characterized a novel human ATP-binding cassette (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, confering resistance to chemotherapy in vitro. 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. In tandem with fundamental approaches to further establish ABCB5 as an identifier of melanoma stem cells and to characterize the functional roles of ABCB5 in physiological and cancer stem cells, Dr. Frank’s laboratory explores the clinical relevance of ABCB5 as a biomarker of melanoma progression, prognosis, and outcome, and to investigate the therapeutic efficacy of ABCB5 targeting in preclinical animal models of human malignant melanoma.

Publications

• Schatton T, Murphy GF, Frank NY, Yamaura K, Waaga-Gasser AM, Gasser M, Zhan Q, Jordan S, Duncan LM, Weishaupt C, Fuhlbrigge RC, Kupper TS, Sayegh MH, Frank MH. Identification of cells initiating human melanomas. Nature 2008 Jan 17; 451(7176):345-9
  PMID: 18202660
• Pendse SS, Behjati S, Schatton T, Izawa A, Sayegh MH, Frank MH. P-glycoprotein functions as a differentiation switch in antigen presenting cell maturation. Am J Transplant 2006 Dec; 6(12):2884-93
  PMID: 17083370
• Frank NY, Kho AT, Schatton T, Murphy GF, Molloy MJ, Zhan Q, Ramoni MF, Frank MH, Kohane IS, Gussoni E. Regulation of myogenic progenitor proliferation in human fetal skeletal muscle by BMP4 and its antagonist Gremlin. J Cell Biol 2006 Oct 9; 175(1):99-110
  PMID: 17015616
• Frank NY, Margaryan A, Huang Y, Schatton T, Waaga-Gasser AM, Gasser M, Sayegh MH, Sadee W, Frank MH. ABCB5-mediated doxorubicin transport and chemoresistance in human malignant melanoma. Cancer Res 2005 May 15; 65(10):4320-33
  PMID: 15899824
• Frank MH, Sayegh MH. Immunomodulatory functions of mesenchymal stem cells. Lancet 2004 May 1; 363(9419):1411-2
  PMID: 15121399
• Frank NY, Pendse SS, Lapchak PH, Margaryan A, Shlain D, Doeing C, Sayegh MH, Frank MH. Regulation of progenitor cell fusion by ABCB5 P-glycoprotein, a novel human ATP-binding cassette transporter. J Biol Chem 2003 Nov 21; 278(47):47156-65
  PMID: 12960149
• Frank MH, Denton MD, Alexander SI, Khoury SJ, Sayegh MH, Briscoe DM. Specific MDR1 P-glycoprotein blockade inhibits human alloimmune T cell activation in vitro. J Immunol 2001 Feb 15; 166(4):2451-9
  PMID: 11160305
• Lutz NW, Franks SE, Frank MH, Pomer S, Hull WE. Investigation of multidrug resistance in cultured human renal cell carcinoma cells by 31P-NMR spectroscopy and treatment survival assays. MAGMA 2005 Jul; 18(3):144-61
  PMID: 15977034
• Lapchak PH, Melter M, Pal S, Flaxenburg JA, Geehan C, Frank MH, Mukhopadhyay D, Briscoe DM. CD40-induced transcriptional activation of vascular endothelial growth factor involves a 68-bp region of the promoter containing a CpG island. Am J Physiol Renal Physiol 2004 Sep; 287(3):F512-20
  PMID: 15140761
• Pendse S, Sayegh MH, Frank MH. P-glycoprotein--a novel therapeutic target for immunomodulation in clinical transplantation and autoimmunity? Curr Drug Targets 2003 Aug; 4(6):469-76
  PMID: 12866661
• Frank MH, Pomer S. Interferon alpha2b differentially affects proliferation of two human renal cell carcinoma cell lines differing in the P-glycoprotein-associated multidrug-resistant phenotype. J Cancer Res Clin Oncol 1999; 125(2):117-20
  PMID: 10190320