ZIA BC 008756 (ZIA) | |||
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Title | Genetically Engineered Mouse Models to Study RTK Function in Melanoma | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Merlino, Glenn | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $743,463 | Project Dates | 00/00/0000 - 00/00/0000 |
Fiscal Year | 2016 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Metastasis (70.0%) |
Melanoma (100.0%) | ||
Research Type | |||
Cancer Progression & Metastasis Development and Characterization of Model Systems |
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Abstract | |||
The Cancer Modeling Section seeks to elucidate the complex molecular/genetic program governing melanoma genesis and progression through the development and analysis of genetically engineered mouse models of human cancer. Exposure to ultraviolet radiation (UV) is a causal agent in the vast majority of melanoma. 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). We discovered that a single neonatal dose of burning UV in these mice was necessary and sufficient to induce tumors reminiscent of human melanoma with shortened latency (Noonan et al., Nature 413: 271-2, 2001). A critical role for the INK4A/ARF locus, which helps regulate the pRb and p53 pathways and is widely regarded as a key melanoma suppressor in human patients, was also confirmed in our animal model (Recio et al., Cancer Res. 62: 6724-30, 2002). There has been controversy surrounding the relative risks associated with UVB versus UVA radiation. We used albino HGF transgenic mouse to show that UVB, but not UVA, alone is able to induce the full melanoma phenotype in the absence of pigment (DeFabo et al., Cancer Res. 64: 6372-6, 2004). However, we more recently showed that UVA is highly melanomagenic in pigmented HGF/SF-transgenic mice (Noonan et al., Nat. Commun. 3: 884, 2012), demonstrating that melanin is associated with oxidative DNA damage and mutagenesis, and thus represents a double-edged sword with respect to melanoma risk. Our work suggests that indoor tanning, which is mostly UVA-based, could be a significant health risk. We have also employed in vitro and in vivo models based on genetically engineered melanocytes to identify novel regulators of differentiation, malignancy and metastasis. We have, in collaboration with Jim McMahon and Curt Henrich (Molecular Targets Development Program), begun re-exploring the prospects of ""differentiation therapy"". INK4A/ARF-deficient melanocytes transformed by mutant NRAS were used in a high-throughput screen of the LOPAC drug library to identify agents that would induce re-differentiation of malignant melanoma cells, thus converting them to a more benign state. Eight candidate drugs were identified that induce a differentiated morphology. Interestingly, several of these candidates were related to dopaminergic signaling, including inhibitors of DOPA decarboxylase (DDC), which we found to be upregulated in melanomas and are used for other indications in the clinic. Dopamine not only controls the biosynthesis and secretion of melanotropins, but also helps regulate the activity of cAMP, which is also linked to melanin production. The differentiating activity of these compounds was confirmed in mouse and human melanoma cells. Notably, we found that several of these compounds effectively reduced the ability of melanoma cells to invade and grow under anchorage-independent conditions. The data suggest that re-differentiating drugs can also have anti-tumorigenic properties. Although an extensive accumulation of epidemiological evidence supports a fundamental role for UV in melanoma, the specific UV-affected molecular pathways and mechanisms remain largely unidentified. We have suggested that mechanisms other than UV-induced DNA mutagenesis may also be important in melanoma initiation. To determine the role(s) of UV in melanoma in vivo, we developed a mouse model (iDCT-GFP) that allows melanocytes, specifically and inducibly labeled with green fluorescent protein (GFP), to be highly purified from disaggregated mouse skin by FACS following UV irradiation in vivo. We identified a pattern of UVB induced gene expression changes in melanocytes isolated from mice that are consistent with inflammatory alterations and may spare melanocytes post-UV remodeling-associated destruction. We have identified an interferon (IFN)-gamma signaling signature arising in melanocytes after neonatal UV |