An investigation of the role of two novel cancer targets, P-Rex1 and FAK, in genetically modified mouse models of melanoma

R Medicine (General);RL Dermatology;RM Therapeutics. Pharmacology

Lindsay, Colin Rowan ; Sansom, Owen

University:University of Glasgow

Department:Institute of Cancer Sciences

关键词: R Medicine (General);    RL Dermatology;    RM Therapeutics. Pharmacology;   

Others  :  http://theses.gla.ac.uk/3772/1/2012lindsayphd.pdf

来源: University of Glasgow

【 摘 要 】

Background: Metastases are the major cause of death from melanoma, a skin cancer which has the fastest rising incidence of any malignancy in the Western world. Molecular pathways that drive melanoblast migration in development are believed to underpin the movement and ultimately the metastasis of melanoma. Aims: In this thesis we use genetically modified mice models to characterise two novel anticancer targets, P-Rex1 and focal adhesion kinase (FAK). Embryonic melanoblast migration is compared with cancer outcomes for each genetic modification.Results: Mice lacking P-Rex1, a Rac-specific Rho GTPase guanine nucleotide exchange factor (GEF), have a melanoblast migration defect during development evidenced by a white belly. These P-Rex1-/- mice are resistant to metastasis when crossed to a murine model of melanoma, an effect specifically channeled through loss of P-Rex1 GEF activity. FAK disruption compromises melanoblast cell numbers and migration in development, but has no long-term effect on melanocyte homeostasis. FAK-deleted mice have a divergent role in melanomagenesis, delaying primary melanoma onset whilst promoting metastasis following disease onset. Conclusions: We conclude that P-Rex1 and FAK play important roles in melanoblast embryology and melanoma development and progression. Both P-Rex1 and FAK represent interesting therapeutic targets for the treatment of cancer.