Our laboratory seeks to elucidate the complex molecular/genetic program governing tumor genesis and progression through the development and analysis of genetically engineered mouse models of human cancer. A major goal is to identify candidate targets or pathways for both mechanistic enlightenment and therapeutic utility. Our efforts in this regard are focused on two tumor types, cutaneous malignant melanoma (CMM) and the pediatric malignancy rhabdomyosarcoma (RMS). Exposure to UV radiation is a causal agent in the vast majority of CMM. Retrospective epidemiological data have suggested that CMM is provoked by intense but intermittent exposure to UV, particularly during childhood. We tested this hypothesis in genetically engineered mice in which the receptor tyrosine kinase c-MET was deregulated by virtue of ectopic expression of its ligand, hepatocyte growth factor/scatter factor (HGF/SF). We discovered that a single neonatal dose of burning UV radiation in these mice was necessary and sufficient to induce tumors reminiscent of human CMM (Noonan et al., Nature 413: 271-2, 2001). A critical role for the INK4a/ARF locus, widely regarded as a key melanoma suppressor in human patients, was confirmed in our mouse model by demonstrating that UV-induced melanoma was significantly accelerated on a genetic background deficient in Ink4a/Arf (Recio et al., Cancer Res. 62: 6724-30, 2002). These results strongly suggest that sunburn is a highly significant risk factor in kindreds harboring germline mutations in INK4a/ARF (Merlino and Noonan, Trends Mol. Med. 9: 102-8, 2003). There has been much controversy surrounding the relative risks associated with UVB versus UVA radiation. We used the HGF/SF transgenic mouse to show that UVB, but not UVA, alone is able to induce the full melanoma phenotype (DeFabo et al., Cancer Res. 64: 6372-6, 2004). Preliminary data now suggest that UV-induced mouse melanoma can by prevented by SPF15 sunscreen, demonstrating the potential value of this model system for the development of more effective melanoma prevention strategies.The childhood malignancy RMS, accounting for up to 10% of all pediatric neoplasms and for more than 50% of pediatric soft tissue sarcomas, is believed to arise from imbalances in skeletal muscle cell proliferation and differentiation. However, molecular pathways associated with RMS are poorly understood, due in part to the lack of an RMS-prone animal model. We have discovered that virtually all HGF/SF transgenic, Ink4a/Arf-deficient mutant mice rapidly succumbed to highly invasive RMS (Sharp et al., Nature Med. 8: 1276-80, 2002). Comparable molecular lesions have also been described for human RMS. These data provide genetic evidence that c-MET and INK4a/ARF pathways represent critical and synergistic targets in RMS pathogenesis, and suggest a rational therapeutic combination to combat this pediatric cancer. We have generated highly and poorly metastatic cell lines from the RMS tumors arising in our HGF/SF-transgenic, Ink4a/Arf-deficient mice, which have been a valuable tool for identifying genes regulating metastasis. cDNA microarray analysis has identified a set of genes whose expression was significantly different between highly and poorly metastatic cells. Functional in vivo studies confirmed that the cytoskeletal linker Ezrin and the homeodomain-containing transcription factor Six1 have essential roles in determining the metastatic fate of RMS cells (Yu et al., Nature Med. 10: 175-81). Notably, EZRIN and SIX1 expression levels were also enhanced in human RMS tissue, significantly correlating with clinical stage. Subsequent analyses showed that the Ezrin gene was a direct transcriptional target of Six1, and indispensable for Six1-induced metastasis (manuscript under review).

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC008756-18
Application #
7291910
Study Section
(LCRC)
Project Start
Project End
Budget Start
Budget End
Support Year
18
Fiscal Year
2005
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Fisher, David E; Medrano, Estela E; McMahon, Martin et al. (2008) Meeting report: fourth international congress of the Society for Melanoma Research. Pigment Cell Melanoma Res 21:15-26
Booth, Brian W; Jhappan, Chamelli; Merlino, Glenn et al. (2007) TGFbeta1 and TGFalpha contrarily affect alveolar survival and tumorigenesis in mouse mammary epithelium. Int J Cancer 120:493-9
Merlino, Glenn; Khanna, Chand (2007) Fishing for the origins of cancer. Genes Dev 21:1275-9
Gareau, Daniel S; Merlino, Glenn; Corless, Christopher et al. (2007) Noninvasive imaging of melanoma with reflectance mode confocal scanning laser microscopy in a murine model. J Invest Dermatol 127:2184-90
Yu, Yanlin; Davicioni, Elai; Triche, Timothy J et al. (2006) The homeoprotein six1 transcriptionally activates multiple protumorigenic genes but requires ezrin to promote metastasis. Cancer Res 66:1982-9
Tormo, Damia; Ferrer, Aleix; Gaffal, Evelyn et al. (2006) Rapid growth of invasive metastatic melanoma in carcinogen-treated hepatocyte growth factor/scatter factor-transgenic mice carrying an oncogenic CDK4 mutation. Am J Pathol 169:665-72
Schoeffner, Daniel J; Matheny, Shannon L; Akahane, Takemi et al. (2005) VEGF contributes to mammary tumor growth in transgenic mice through paracrine and autocrine mechanisms. Lab Invest 85:608-23
Gareau, Daniel S; Lagowski, James; Rossi, Vincent M et al. (2005) Imaging melanoma in a murine model using reflectance-mode confocal scanning laser microscopy and polarized light imaging. J Investig Dermatol Symp Proc 10:164-9
Ha, Linan; Noonan, Frances P; De Fabo, Edward C et al. (2005) Animal models of melanoma. J Investig Dermatol Symp Proc 10:86-8
Otsuka, Toshiyuki; Horiguchi, Norio; Kanda, Daisuke et al. (2005) Overexpression of NK2 inhibits liver regeneration after partial hepatectomy in mice. World J Gastroenterol 11:7444-9

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