Final Activity Report Summary - MOUSE MELANOMA MODEL (Characterization of novel acting mechanisms of the Hepatocyte Growth Factor (HGF) in melanomagenesis: ...the HGF transgenic animal model) Even though melanoma is the less frequent skin cancer it is very likely to metastasise and lead to fatal consequences. During the pass thirty years its incidence has increased significantly and that it has a very poor response to the currently available therapies. In a continued effort from the scientific community to better understand this disease, in the last decade several animal melanoma models have been developed and a number of molecules have been implicated with its tumour biology. Among models, the hepatocyte growth factor (HGF) transgenic mouse melanoma model induced by ultraviolet (UV) irradiation represents a good opportunity to understand the molecular bases of this aggressive and heterogeneous disease. This mouse model recapitulates chronologically and histopathologically the human counterpart in all the stages of tumour progression, including metastases. If we compile all the information from the rest of mouse models and the genetic alterations found in human melanoma, it seems that in the HGF transgenic mouse the UV irradiation and the broadly expressed HGF are able to mimic all the major genetic alterations found in human melanoma (i.e. amplifications of Cyclin D1, Cdk4, PTEN deletions) and the activation of the most relevant molecular pathways implicated in melanoma development and progression such as Ras and PI3K pathways. Once the melanocytes has been UV irradiated, HGF achieves this effect by the constitutive activation of the Ras and PI3K pathways through c-Met (receptor tyrosine kinase at the cell surface for HGF, that is also amplified in human melanoma), promoting proliferation motility and survival among other biological responses. Interestingly, the other mouse melanoma models that have been developed having as a first genetic modification one of the relevant molecules found in human melanoma (RasVal12, PTEN and p16Ink4a / ARF deletions) should have another second genetic lesion and / or a tumour promoter treatment (TPA, DMBA, UV) in order to develop melanoma, and when they do, they are mostly dermal and few of them metastasised. All these results indicate that, somehow UV irradiation and the broadly expressed HGF in the mouse set up the appropriate scenario for melanoma development and progression. We tried to identify the phospho-proteins that directly responded to the HGF triggering in the melanoma cells to better understand the underlying biochemical and molecular mechanisms of the melanoma cells derived from tumours arising in the mouse model. We identified 56 proteins that become phosphorylated in response to HGF within the first 10 min after triggering. These identified proteins, some known and others unknown, were participating in the HGF signalling in melanoma cells. We chose two of the identified proteins for future work. We then studied the possible role of these two proteins in biological processes and the signalling pathways responsible for their modification. The discovering of the pathway(s) involved in the post-translational modification induced by HGF is critical for future molecular interventions to avoid the effects mediated by these proteins.
