Associated Project 1

1. Applicant

2. Topic

Molecular characterization of the grm1 mouse model for melanoma

3. Short summary

Mouse models are essential both for the understanding of the biology of disease as well as testing new therapeutic approaches. Until recently no adequate genetic melanoma mouse models were available. One of these newly developed models is the metabotropic glutamate receptor 1 (Grm1)-transgenic mouse which develops melanoma with high penetrance over a predictable time course. Stimulation of the ectopically expressed Grm1 results in activation of the MAPK pathway. Phenotypically, the mice are characterized by melanocyte persistence in the skin, their expansion in a nevus-like pattern, and subsequent malignant transformation. Notably, both the histological morphology as well as the metastatic pattern of these tumors closely resembles human melanoma. Consequently, this murine model allows a timed analysis of melanomagenesis which should reveal the orchestration of the molecular steps necessary for malignant transformation of melanocytic cells. To this end, critical signalling pathways involved in cell cycle regulation, apoptosis and melanocytic differentiation (e.g. AKT, RB, IAPs and MITF) will be addressed. Besides descriptive analyses (immunohistochemistry, quantitative PCR, genomic sequencing, promoter methylation studies) functional assays using Grm1 melanoma cell lines to examine possible molecular changes by siRNA knock down of gene expression or reactivation of inactivated genes by cDNA vectors will be performed in vitro; additional in vivo experiments will be possible by treatment of the animals with specific small molecule signal transduction inhibitors during the course of melanomagenesis. The expected results of these experiments will not only provide an improved understanding of melanomagenesis, but will set the stage for future therapeutic interventions in the clinic.