Photo of Markus H. Frank,   M.D.

Markus H. Frank, M.D.

Brigham And Women's Hospital

Brigham And Women's Hospital
Phone: (617) 919-2993
Fax: (617) 730-0129


Markus.Frank@childrens.harvard.edu

Markus H. Frank, M.D.

Brigham And Women's Hospital

EDUCATIONAL TITLES

  • Assistant Professor, Pediatrics, Harvard Medical School
  • Assistant Professor, Dermatology, Harvard Medical School
  • Associate Physician, Medicine, Brigham And Women's Hospital
  • Member, Stem Cell Program, Boston Children's Hospital

DF/HCC PROGRAM AFFILIATION

Research Abstract

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.

Publications

Powered by Harvard Catalyst
  • Gray ES, Reid A, Bowyer S, Calapre L, Siew K, Pearce R, Cowell L, Frank MH, Millward M, Ziman M. Circulating Melanoma Cell Subpopulations: Their Heterogeneity and Differential Responses to Treatment. J Invest Dermatol 2015. PubMed
  • de Waard NE, Kolovou PE, McGuire SP, Cao J, Frank NY, Frank MH, Jager MJ, Ksander BR. Expression of Multidrug Resistance Transporter ABCB5 in a Murine Model of Human Conjunctival Melanoma. Ocul Oncol Pathol 2015; 1:182-189. PubMed
  • Frank MH, Frank NY. Restoring the cornea from limbal stem cells. Regen Med 2015; 10:1-4. PubMed
  • Lee CW, Zhan Q, Lezcano C, Frank MH, Huang J, Larson AR, Lin JY, Wan MT, Lin PI, Ma J, Kleffel S, Schatton T, Lian CG, Murphy GF. Nestin depletion induces melanoma matrix metalloproteinases and invasion. Lab Invest 2014. PubMed
  • Wilson BJ, Saab KR, Ma J, Schatton T, Pütz P, Zhan Q, Murphy GF, Gasser M, Waaga-Gasser AM, Frank NY, Frank MH. ABCB5 Maintains Melanoma-Initiating Cells through a Proinflammatory Cytokine Signaling Circuit. Cancer Res 2014; 74:4196-207. PubMed
  • Ksander BR, Kolovou PE, Wilson BJ, Saab KR, Guo Q, Ma J, McGuire SP, Gregory MS, Vincent WJ, Perez VL, Cruz-Guilloty F, Kao WW, Call MK, Tucker BA, Zhan Q, Murphy GF, Lathrop KL, Alt C, Mortensen LJ, Lin CP, Zieske JD, Frank MH, Frank NY. ABCB5 is a limbal stem cell gene required for corneal development and repair. Nature 2014; 511:353-7. PubMed
  • Volpicelli ER, Lezcano C, Zhan Q, Girouard SD, Kindelberger DW, Frank MH, Frank NY, Crum CP, Murphy GF. The multidrug-resistance transporter ABCB5 is expressed in human placenta. Int J Gynecol Pathol 2013; 33:45-51. PubMed
  • Murphy GF, Wilson BJ, Girouard SD, Frank NY, Frank MH. Stem cells and targeted approaches to melanoma cure. Mol Aspects Med 2013. PubMed
  • Lin JY, Zhang M, Schatton T, Wilson BJ, Alloo A, Ma J, Qureshi AA, Frank NY, Han J, Frank MH. Genetically determined ABCB5 functionality correlates with pigmentation phenotype and melanoma risk. Biochem Biophys Res Commun 2013. PubMed
  • Nedosekin DA, Sarimollaoglu M, Galanzha EI, Sawant R, Torchilin VP, Verkhusha VV, Ma J, Frank MH, Biris AS, Zharov VP. Synergy of photoacoustic and fluorescence flow cytometry of circulating cells with negative and positive contrasts. J Biophotonics 2013; 6:425-34. PubMed
  • Reid AL, Millward M, Pearce R, Lee M, Frank MH, Ireland A, Monshizadeh L, Rai T, Heenan P, Medic S, Kumarasinghe P, Ziman M. Markers of circulating tumour cells in the peripheral blood of patients with melanoma correlate with disease recurrence and progression. Br J Dermatol 2013; 168:85-92. PubMed
  • Cedeno-Laurent F, Opperman MJ, Barthel SR, Hays D, Schatton T, Zhan Q, He X, Matta KL, Supko JG, Frank MH, Murphy GF, Dimitroff CJ. Metabolic Inhibition of Galectin-1-Binding Carbohydrates Accentuates Antitumor Immunity. J Invest Dermatol 2011. PubMed
  • Wilson BJ, Schatton T, Zhan Q, Gasser M, Ma J, Saab KR, Schanche R, Waaga-Gasser AM, Gold JS, Huang Q, Murphy GF, Frank MH, Frank NY. ABCB5 identifies a therapy-refractory tumor cell population in colorectal cancer patients. Cancer Res 2011. PubMed
  • Ho J, Pandey P, Schatton T, Sims-Lucas S, Khalid M, Frank MH, Hartwig S, Kreidberg JA. The Pro-Apoptotic Protein Bim Is a MicroRNA Target in Kidney Progenitors. J Am Soc Nephrol 2011; 22:1053-63. PubMed
  • Wilson BJ, Schatton T, Frank MH, Frank NY. Colorectal Cancer Stem Cells: Biology and Therapeutic Implications. 2011; 7:128-135. PubMed
  • Laga AC, Zhan Q, Weishaupt C, Ma J, Frank MH, Murphy GF. SOX2 and nestin expression in human melanoma: an immunohistochemical and experimental study. Exp Dermatol 2011; 20:339-45. PubMed
  • Frank NY, Schatton T, Kim S, Zhan Q, Wilson BJ, Ma J, Saab KR, Osherov V, Widlund HR, Gasser M, Waaga-Gasser AM, Kupper TS, Murphy GF, Frank MH. VEGFR-1 expressed by malignant melanoma initiating cells is required for tumor growth. Cancer Res 2011. PubMed
  • Ma J, Lin JY, Alloo A, Wilson BJ, Schatton T, Zhan Q, Murphy GF, Waaga-Gasser AM, Gasser M, Hodi FS, Frank NY, Frank MH. Isolation of tumorigenic circulating melanoma cells. Biochem Biophys Res Commun 2010; 402:711-7. PubMed
  • Schatton T, Frank MH. The in vitro spheroid melanoma cell culture assay: cues on tumor initiation? J Invest Dermatol 2010; 130:1769-71. PubMed
  • Izawa A, Schatton T, Frank NY, Ueno T, Yamaura K, Pendse SS, Margaryan A, Grimm M, Gasser M, Waaga-Gasser AM, Sayegh MH, Frank MH. A novel in vivo regulatory role of P-glycoprotein in alloimmunity. Biochem Biophys Res Commun 2010; 394:646-52. PubMed
  • Ma J, Frank MH. Tumor initiation in human malignant melanoma and potential cancer therapies. Anticancer Agents Med Chem 2010; 10:131-6. PubMed
  • Schatton T, Schütte U, Frank NY, Zhan Q, Hoerning A, Robles SC, Zhou J, Hodi FS, Spagnoli GC, Murphy GF, Frank MH. Modulation of T-Cell Activation by Malignant Melanoma Initiating Cells. Cancer Res 2010; 70:697-708. PubMed
  • Frank NY, Schatton T, Frank MH. The therapeutic promise of the cancer stem cell concept. J Clin Invest 2010; 120:41-50. PubMed
  • Frank NY,Frank MH. ABCB5 gene amplification in human leukemia cells. Leuk Res 2009; 33:1303-5. PubMed
  • Schatton T, Frank NY, Frank MH. Identification and targeting of cancer stem cells. Bioessays 2009; 31:1038-49. PubMed
  • Schatton T, Frank MH. Antitumor immunity and cancer stem cells. Ann N Y Acad Sci 2009; 1176:154-69. PubMed
  • Behjati S, Frank MH. The effects of tamoxifen on immunity. Curr Med Chem 2009; 16:3076-80. PubMed
  • Schatton T, Frank MH. Cancer stem cells and human malignant melanoma. Pigment Cell Melanoma Res 2008; 21:39-55. PubMed
  • 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; 451:345-9. PubMed
  • 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; 6:2884-93. PubMed
  • 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; 175:99-110. PubMed
  • 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; 18:144-61. PubMed
  • 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; 65:4320-33. PubMed
  • 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; 287:F512-20. PubMed
  • Frank MH, Sayegh MH. Immunomodulatory functions of mesenchymal stem cells. Lancet 2004; 363:1411-2. PubMed
  • 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; 278:47156-65. PubMed
  • Pendse S, Sayegh MH, Frank MH. P-glycoprotein--a novel therapeutic target for immunomodulation in clinical transplantation and autoimmunity? Curr Drug Targets 2003; 4:469-76. PubMed
  • Pendse SS, Briscoe DM, Frank MH. P-glycoprotein and alloimmune T-cell activation. 2011; 4:3-14. PubMed
  • 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; 166:2451-9. PubMed
  • 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; 125:117-20. PubMed
  • Kellner H, Liegl U, Frank M, Zoller WG. [Reversible esophageal dysfunction as a side effect of levodopa] 1996; 63:48-50. PubMed
Hide