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. 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 intermittent, intense exposure to UV, particularly during childhood. Previously, we tested this hypothesis in transgenic mice in which the receptor tyrosine kinase 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 with shortened latency (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 animal model by demonstrating that UV-induced melanoma was significantly accelerated in Ink4a/Arf-deficient mice (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 controversy surrounding the relative risks associated with UVB versus UVA radiation. We used albino 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). Recent data also 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 MET and INK4a/ARF pathways represent critical and synergistic targets in RMS pathogenesis, and suggest a rational therapeutic combination to combat this pediatric cancer. A panel of highly and poorly metastatic cell lines generated from RMS tumors arising in our mouse model was used in concert with expression profiling to identify a set of genes associated with enhanced metastasis. 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, 2004). Notably, EZRIN and SIX1 expression levels were also both enhanced in human RMS tissue, significantly correlating with clinical stage. Subsequent analyses showed that the Ezrin gene was in fact a direct transcriptional target of Six1, and indispensable for Six1-induced metastasis (Yu et al., Cancer Res. 66: 1982-9, 2006). Further analysis revealed that Six1 regulates Ezrin expression through epigenetic modification of Ezrin gene chromatin. Ezrin appears to represent a very promising therapeutic target for patients with advanced stage RMS.The relevance of the p53- and pRb-tumor suppressor pathways to the development of most, if not all types of cancer is unequivocal.
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