The Cancer Modeling Section 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 primarily on cutaneous malignant melanoma. Exposure to ultraviolet (UV) radiation is a causal agent in the vast majority of melanoma. Retrospective epidemiological data have suggested that melanoma 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 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 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). HGF/SF transgenic mice harboring an oncogenic mutation in CDK4, carried by some melanoma-prone kindreds, also exhibited highly accelerated melanoma genesis (Tormo et al., Am. J. Pathol. 169: 665-72, 2006). There has been controversy surrounding the relative risks associated with UV-B versus UV-A radiation. We used albino HGF/SF transgenic mouse to show that UV-B, but not UV-A, alone is able to induce the full melanoma phenotype (DeFabo et al., Cancer Res. 64: 6372-6, 2004). Remarkably, our most recent results indicate clearly that in pigmented HGF/SF-transgenic mice, UV-A is highly melanomagenic (Noonan et al., revision submitted), demonstrating the melanin is a double-edged sword with respect to melanoma risk. The relevance of the p53- and pRb-tumor suppressor pathways to the development of most, if not all types of cancer is unequivocal. However, critical questions remain concerning the relative roles of specific p53- and pRb-pathway members, and how these roles vary among tumors arising from distinct cellular lineages. In particular, functional differences between p53 and its indirect positive regulator ARF in the suppression of tumorigenesis have not been clarified;p53 is degraded by MDM2, an activity that can be blocked by ARF. Enigmatically, although the most commonly mutated gene in human cancer, p53 does not appear to play a significant role in the development of melanoma. In contrast to p53, ARF is frequently inactivated in melanoma through loss at the INK4A/ARF locus, long associated with heritable susceptibility to melanoma. Using animal- and cell culture-based models of melanoma we found that oncogene-induced senescence, a barrier against early tumor progression, can be overcome by a deficiency in ARF, but not p53, facilitating rapid development of melanoma (Ha et al., Proc. Natl. Acad. Sci. 104: 10968-73, 2007). Accordingly, oncogenic NRAS was found to collaborate with a deficiency in ARF, but not p53, to fully transform melanocytes in vitro. Our data help explain in human melanoma the relative abundance and paucity of mutations in ARF and TP53, respectively, and demonstrate that ARF and p53, although linked in a common pathway, suppress tumorigenesis through diverse, lineage-dependent mechanisms. Thus, therapeutics currently being designed to restore wild-type p53 function may be insufficient to counter melanoma and other malignancies in which ARF holds significant p53-independent tumor suppressor activity (Ha et al., Cell Cycle 7:1944-8, 2008). The downstream targets of ARF are currently being investigated, along with its role in differentiation. We recently compared and contrasted the oncogenic roles of the three major NRas downstream effectors, Raf, PI3K and Ral guanine exchange factor (RalGEF), using our Arf-deficient immortalized mouse melanocytes as a model system (Mishra et al., Oncogene 29:2249-2256, 2010). Although no single downstream pathway could recapitulate all of the consequences of oncogenic NRas expression, our data indicated a prominent role for BRaf and PI3K in melanocyte senescence and invasiveness, respectively. More surprisingly, we discovered that constitutive RalGEF activation had a major impact on several malignant phenotypes, particularly anchorage-independent growth, indicating that this often overlooked pathway should be more carefully evaluated as a possible therapeutic target. 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, limiting the development of successful prevention and treatment strategies. In fact, few specific UV signature mutations such as C to T transitions have been found in genes thought to contribute to melanoma. These uncertainties suggest that mechanisms other than UV-induced DNA mutagenesis may be involved in melanoma initiation. These mechanisms have been difficult to study because UV irradiation of cultured melanocytic cells simply cannot reproduce events in vivo. It is extremely difficult to gauge what levels of UV are comparable to what cells experience in vivo, and more importantly there is no microenvironment in cultured cells, which absolutely must play a role in any response to UV. To help determine the role(s) of UV in melanoma in vivo, we have recently developed an experimental mouse model that allows melanocytes, specifically and inducibly labeled with green fluorescent protein, to be highly purified from disaggregated mouse skin by fluorescence activated cell sorting following UV irradiation in vivo. We have already identified a pattern of UV-B induced gene expression changes in melanocytes isolated from mice that are consistent with inflammatory alterations and may spare melanocytes post-UV remodeling-associated destruction. Specifically, we have identified an interferon (IFN)-gamma signaling signature arising in melanocytes after neonatal UV irradiation. The source was macrophages recruited to the skin after UV exposure;IFN-gamma in turn activated melanocytes and the expression of genes that could facilitate immunoevasive mechanisms. Transplanted neonatal macrophages were found to significantly enhance melanoma growth in vivo in an IFN-g-dependent fashion. This was surprising considering that for years IFN-alpha was used to treat melanoma patients, albeit with very limited success. We hypothesize that melanomas may escape immune destruction by co-opting these pathways already prewired in melanocytes, and suggest that the IFN-gamma signaling pathway may represent a promising new therapeutic target for melanoma patients. We are also subjecting in vivo exposed melanocytes to deep sequencing to try to identify genomic targets of UV radiation. We will use fluorescence activated cell sorting to isolate green fluorescent protein-labeled melanocytes from all stages of melanoma development in an attempt to catalog their precise genomic alterations. We anticipate that this in vivo model will provide novel insights into the nature of UV-induced damage, and the mechanisms by which UV provokes melanoma.

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Huang, Liping; Qin, Yifei; Zuo, Qiang et al. (2018) Ezrin mediates both HGF/Met autocrine and non-autocrine signaling-induced metastasis in melanoma. Int J Cancer 142:1652-1663
Yu, Yanlin; Dai, Meng; Lu, Andrew et al. (2018) PHLPP1 mediates melanoma metastasis suppression through repressing AKT2 activation. Oncogene 37:2225-2236
Zuo, Qiang; Liu, Jing; Huang, Liping et al. (2018) AXL/AKT axis mediated-resistance to BRAF inhibitor depends on PTEN status in melanoma. Oncogene 37:3275-3289
Harris, Melissa L; Fufa, Temesgen D; Palmer, Joseph W et al. (2018) A direct link between MITF, innate immunity, and hair graying. PLoS Biol 16:e2003648
Leachman, Sancy A; Merlino, Glenn (2017) Medicine: The final frontier in cancer diagnosis. Nature 542:36-38
Michael, Helen T; Merlino, Glenn (2017) A Topical Solution to the Sunless Tanning Problem. Trends Mol Med 23:771-773
Mishra, Prasun J; Mishra, Pravin J; Merlino, Glenn (2016) Integrated Genomics Identifies miR-32/MCL-1 Pathway as a Critical Driver of Melanomagenesis: Implications for miR-Replacement and Combination Therapy. PLoS One 11:e0165102
Merlino, Glenn; Herlyn, Meenhard; Fisher, David E et al. (2016) The state of melanoma: challenges and opportunities. Pigment Cell Melanoma Res 29:404-16
Cataisson, Christophe; Michalowski, Aleksandra M; Shibuya, Kelly et al. (2016) MET signaling in keratinocytes activates EGFR and initiates squamous carcinogenesis. Sci Signal 9:ra62
Day, Chi-Ping; Merlino, Glenn; Van Dyke, Terry (2015) Preclinical mouse cancer models: a maze of opportunities and challenges. Cell 163:39-53

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