Glenn Merlino, Ph.D.
Laboratory of Cancer Biology and Genetics
Acting Scientific Director for Basic Research
Building 37, Room 5002
Bethesda, MD 20892-4264
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.
Jhappan C, Stahle C, Harkins RN, Fausto N, Smith GH, Merlino GT. TGF alpha overexpression in transgenic mice induces liver neoplasia and abnormal development of the mammary gland and pancreas. Cell. 1990;61(6):1137-46.
Noonan FP, Recio JA, Takayama H, Duray P, Anver MR, Rush WL, De Fabo EC, Merlino G. Neonatal sunburn and melanoma in mice. Nature. 2001;413(6853):271-2.
Sharp R, Recio JA, Jhappan C, Otsuka T, Liu S, Yu Y, Liu W, Anver M, Navid F, Helman LJ, DePinho RA, Merlino G. Synergism between INK4a/ARF inactivation and aberrant HGF/SF signaling in rhabdomyosarcomagenesis. Nat Med. 2002;8(11):1276-80.
Yu Y, Khan J, Khanna C, Helman L, Meltzer PS, Merlino G. Expression profiling identifies the cytoskeletal organizer ezrin and the developmental homeoprotein Six-1 as key metastatic regulators. Nat Med. 2004;10(2):175-81.
Zaidi MR, Davis S, Noonan FP, Graff-Cherry C, Hawley TS, Walker RL, Feigenbaum L, Fuchs E, Lyakh L, Young HA, Hornyak TJ, Arnheiter H, Trinchieri G, Meltzer PS, De Fabo EC, Merlino G. Interferon-γ links ultraviolet radiation to melanomagenesis in mice. Nature. 2011;469(7331):548-53.