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Glenn Merlino, Ph.D.

Senior Investigator
Laboratory of Cancer Biology and Genetics
NCI/CCR
Building 37, Room 5002
Bethesda MD, 20892-4264
301-496-4270

Research Topics

Modeling the Genesis and Progression of Human Melanoma in the Mouse
The major goal of the Cancer Modeling Section of the Laboratory of Cancer Biology and Genetics is to elucidate the complex molecular and genetic programs governing tumor initiation and metastatic progression through the development and analysis of better, more relevant genetically engineered mouse models of human cancer. Our aim is to employ such mouse models, and the tissues and cells derived from them, to uncover the molecular mechanisms underlying these processes, and identify candidate factors or pathways that may ultimately serve as therapeutic targets in patients. Our research efforts in this regard have been focused predominantly on cutaneous malignant melanoma for several reasons. Melanoma is an extremely aggressive, often fatal disease that has proven to be largely resistant to currently available therapeutic approaches. Compounding this health hazard, the incidence of melanoma has steadily increased over the last 40 years, and continues to rise at a time when the incidence of many other cancers is falling. Melanoma is particularly well suited to our major research interests. Its etiological initiating factor, ultraviolet (UV) radiation, is long known but its role in melanoma genesis remains poorly understood. Moreover, its propensity to metastasize, even years after removal of the original primary tumor, makes this cancer especially deadly. We have created a mouse model, based on deregulated signaling of the receptor tyrosine kinase MET, that when provoked by UV radiation develops melanocytic lesions in stages that are highly reminiscent of human melanoma with respect to both histopathologic architecture and molecular wiring. This mouse is being used to experimentally address questions that have long perplexed the melanoma research community: is childhood sunburn a significant melanoma risk factor; is UV-B or UV-A the more influential melanoma agent; does sunblock prevent melanoma genesis? We are currently using this mouse model to determine what UV radiation actually does to melanocytes and how it induces melanoma genesis. For example, by designing mice in which melanocytes express green fluorescent protein in a tetracycline-inducible fashion, we can use fluorescence-activated cell sorting to isolate melanocytes from mice following UV irradiation and subject them to detailed molecular analyses, including array-based expression profiling and deep sequencing to search for mutations. Other mice we have generated in which Cre recombinase is conditionally targeted to melanocytes are allowing us to determine which tumor suppressor genes prevent progression from each stage of melanoma. We are particularly interested in mechanisms associated with the spread and survival of metastatic cells. All data derived from mouse melanomas are compared with their human counterparts to determine the relevance of our findings. Ultimately, we plan to use our melanoma mouse model to perform preclinical studies, aimed at an examination of the role of cancer stem cells in drug-resistant residual metastatic disease.

Our collaborators include Ron DePinho, Dana-Farber Cancer Institute; Frances Noonan and Ed DeFabo, George Washington University; Paul Meltzer, NCI; Giorgio Trinchieri, NCI.

Biography

Dr. Merlino obtained his B.A. summa cum laude in 1975, then went on to receive his Ph.D. in 1980 from the Department of Cellular and Molecular Biology at the University of Michigan. He has served as the NIH Ombudsman for Animal Welfare, on the Editorial Board of Cancer Research, on the Steering Committees of the Center of Excellence in Integrative Cancer Biology and Genomics and CCR Science Board, and as Executive Editor of Pigment Cell and Melanoma Research. Dr. Merlino is currently a CCR Deputy Director.

Selected Publications

  1. Praetorius C, Grill C, Stacey SN, Metcalf AM, Gorkin DU, Robinson KC, Van Otterloo E, Kim RS, Bergsteinsdottir K, Ogmundsdottir MH, Magnusdottir E, Mishra PJ, Davis SR, Guo T, Zaidi MR, Helgason AS, Sigurdsson MI, Meltzer PS, Merlino G, Petit V, Larue L, Loftus SK, Adams DR, Sobhiafshar U, Emre NC, Pavan WJ, Cornell R, Smith AG, McCallion AS, Fisher DE, Stefansson K, Sturm RA, Steingrimsson E. A polymorphism in IRF4 affects human pigmentation through a tyrosinase-dependent MITF/TFAP2A pathway. Cell. 2013;155(5):1022-33.
  2. Wilson W 3rd, Merlino G. Flipping the phenotypic switch on a novel antimelanoma differentiation strategy. Pigment Cell Melanoma Res. 2013;26(6):791-3.
  3. Merlino G, Flaherty K, Acquavella N, Day CP, Aplin A, Holmen S, Topalian S, Van Dyke T, Herlyn M. Meeting report: The future of preclinical mouse models in melanoma treatment is now. Pigment Cell Melanoma Res. 2013;26(4):E8-E14.
  4. Moustafa ME, Carlson BA, Anver MR, Bobe G, Zhong N, Ward JM, Perella CM, Hoffmann VJ, Rogers K, Combs GF Jr, Schweizer U, Merlino G, Gladyshev VN, Hatfield DL. Selenium and selenoprotein deficiencies induce widespread pyogranuloma formation in mice, while high levels of dietary selenium decrease liver tumor size driven by TGFα. PLoS One. 2013;8(2):e57389.
  5. Van Dyke T, Merlino G. β-catenin in metastatic melanoma--the smoking gun reloaded. Pigment Cell Melanoma Res. 2012;25(2):125-6.
This page was last updated on April 1st, 2014