Research efforts within the Molecular Genetics Section are focused on the development and exploitation of genetically engineered mouse models of human melanoma and other cancers. Our major goal is to create lines of transgenic mice that will be useful as basic cancer research tools, and that will ultimately serve as pre-clinical cancer models. Exposure to UV radiation is thought to be a causal agent in the vast majority of cutaneous malignant melanomas (CMM). Retrospective epidemiological data suggest that CMM is provoked by intense intermittent exposure to UV, particularly during childhood. We tested this hypothesis in mice in which expression of a transgene encoding the c-Met ligand, hepatocyte growth factor/scatter factor (HGF/SF), induced sporadic melanocytic tumors in aged animals. We discovered that a single neonatal dose of reddening, erythemal UV radiation was necessary and sufficient to induce cutaneous melanoma with high penetrance and relatively short latency, arising with histopathologic and molecular pathogenetic profiles remarkably reminiscent of human melanoma (Noonan et al., Nature 413: 271-272, 2001). These data provide the first experimental validation of epidemiological evidence that childhood sunburn represents a high risk with respect to CMM. A critical role for INK4a/ARF, widely regarded as a key melanoma suppressor in human patients, in our HGF/SF transgenic mouse model was confirmed by demonstrating that UV-induced melanoma was significantly accelerated on a genetic background deficient in Ink4a/Arf. These results strongly suggest that sunburn is a significant risk factor in kindreds harboring germ-line mutations in INK4a/ARF. The childhood malignancy rhabdomyosarcoma (RMS) is thought to arise from imbalances in skeletal muscle cell proliferation and differentiation. However, molecular pathways associated with RMS remain largely unknown, due in large part to the lack of an RMS-prone mouse model. In the course of studying genetic interactions between c-MET and the INK4a/ARF locus, we discovered that virtually all HGF/SF transgenic, ink4a/arf null mutant mice rapidly succumbed to highly invasive 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 devastating childhood cancer. Studies are underway to identify candidate genes responsible for triggering the metastatic phenotype in RMS cells. Normal cells are dependent on exogenous, receptor-mediated growth stimulation to enter the cell cycle and sustain its progression, providing a critical homeostatic mechanism regulating cellular proliferation. In contrast, tumor cells acquire some degree of growth signal autonomy, often through their ability to produce growth factors as well as their receptors (autocrine signaling). Recently, data have begun to emerge implicating heterotypic signaling between diverse cell types within a tumor in the genesis and progression of cancer; however, current experimental approaches in vivo have not adequately addressed this critical relationship. We employed our HGF/SF transgenic mice as genetically modified hosts for transplantation of tumor cells expressing their receptor, c-Met, to directly assess the contribution of heterotypic signaling to metastatic colonization. We found that the incidence of lung metastases under non-autocrine signaling conditions rivaled that observed under conditions of autocrine signaling. Surprisingly, host mice expressing a transgene encoding a natural variant of HGF/SF, NK2, exhibited a shift in metastatic site preference from lung to liver. Our data (Yu and Merlino, Cancer Research 62: 2951-2956, 2002) show that growth factors not intrinsic to malignant cells can have profound effects on metastatic efficiency in vivo, and provide experimental support of a role for heterotypic signaling in tumor progression. It has been argued that genetic instability is required to generate the myriad mutations that fuel tumor initiation and progression and, in fact, patients with heritable cancer susceptibility syndromes harbor defects in genes that normally maintain DNA integrity. However, the vast majority of human cancers arise sporadically, in the absence of deficiencies in known mutator genes. We employed a mutation detection assay based on a lambda bacteriophage reporter gene to show that the mean frequency of forward mutations in mammary adenocarcinomas arising in breast cancer-prone c-erbB2 transgenic mice harboring multiple copies of the lambda genome was significantly higher than in wild type mammary tissue. Analysis of the mutational spectrum within the mammary tumor genomic DNA demonstrated a >6-fold elevation in transversion mutation frequency, resulting in a highly unusual inversion of the transition/transversion ratio characteristic of normal epithelium (Liu et al., Proc. Natl. Acad. Sci. USA 99: 3770-3775, 2002). Data from this model system support the notion that elaboration of a mutator phenotype is a consequential event in breast cancer, and suggest that a novel DNA replication/repair gene is a relatively early mutational target in c-erbB2-induced mammary tumorigenesis
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