Our Science – Merlino Website

Glenn Merlino, Ph.D.

Laboratory of Cancer Biology and Genetics Head, Cancer Modeling Section Laboratory Chief National Cancer Institute Building 37, Room 5002 37 Convent Drive Bethesda, MD 20892-4264 Phone:   301-496-4270 Fax:   301-480-7618 E-Mail:   gmerlino@helix.nih.gov

Biography

After obtaining his B.A. summa cum laude, Dr. Merlino received 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, and is on the Editorial Board of Cancer Research.

Research

Receptor Tyrosine Kinase Signaling in Mouse Models of Human Cancer
Eukaryotic cells communicate through an intricate network of signaling pathways designed to exquisitely regulate cellular activities such as growth, differentiation, migration, and apoptosis. Signaling, and therefore biological response, can be initiated when specific peptide growth factors interact with their high-affinity cell surface receptors, many of which are powerful tyrosine kinases (RTKs) encoded by proto-oncogenes. RTK signal transduction is frequently dysregulated in tumorigenesis. The main aim of the Molecular Genetics Section is to create genetically engineered mice that serve as models of human cancer and to use these models to determine how RTK function is subverted in tumor formation and progression. We have chosen the melanocyte as a model system to study RTKs because it is unusual in its dependency for normal development and function on a multitude of tyrosine kinase receptors, including the hepatocyte growth factor/scatter factor (HGF/SF) receptor c-Met. Moreover, melanocytic tumors deserve extraordinary attention because they are arising with increasing incidence and are among the most aggressive types of human cancer. If untreated, virtually every malignant melanoma has the potential to metastasize, after which patient prognosis is extremely poor.

HGF/SF is a multifunctional factor capable of eliciting mitogenic, motogenic, and morphogenic responses in various c-met-expressing epithelial cells and in melanocytes. Furthermore, c-met is essential for normal embryogenesis, and has been implicated in the development of many human tumors, including malignant melanoma. We have determined that overexpressing an HGF/SF transgene in mice perturbs normal melanocyte development, and induces in aged animals cutaneous malignant melanoma with metastatic capability, a phenotype that is exceedingly rare in mice. Typically, these tumors showed both high expression of transgenic HGF/SF and enhanced c-Met expression and kinase activity, indicating that the creation and selection of cells harboring HGF/SF-Met autocrine signaling loops is the mechanistic basis of tumorigenesis in this transgenic model. We subjected this transgenic mouse model to various regimens of ultraviolet (UV) irradiation to determine experimentally the role of solar radiation in melanomagenesis. We found that chronic adult suberythemal UV irradiation failed to accelerate melanoma formation in HGF/SF-transgenic mice. In contrast, a single dose of neonatal erythrogenic UV radiation induced highly penetrant cutaneous melanoma, arising with a histopathologic and molecular pathogenetic profile remarkably similar to human melanoma. Our data present the first experimental validation of epidemiological evidence that childhood sunburn poses a significant risk for malignant melanoma.

To determine if melanomagenesis can be facilitated by the absence of the INK4a tumor suppressor locus (encoding both 16INK4a and p19ARF), we placed the HGF/SF transgene on an ink4a null background. Unexpectedly, we found that virtually all mice expressing the HGF/SF transgene and deficient for ink4a developed highly invasive, multicentric skeletal muscle tumors by 3.3 months of age. These neoplasms resembled human rhabdomyosarcoma (RMS) morphologically and at the molecular level; both mouse and human RMS demonstrated disruption of the c-MET, pRB, and p53 pathways. This mouse model has provided genetic evidence that c-MET and INK4a/ARF pathways represent critical, synergistic targets in RMS pathogenesis, and that simultaneous disruption of myogenic growth and differentiation drives rhabdomyosarcomagenesis.

Our collaborators include Ronald DePinho, Dana-Farber Cancer Institute; Lee Helman, NIH; and Frances Noonan, George Washington University.

This page was last updated on 6/11/2008.