Pancreatic Cancer and Melanoma Models and Mechanisms

Previous and current research
Our laboratory created two distinct models of early and advanced pancreatic ductal adenocarcinoma (PDA) by conditionally expressing endogenous oncogenic alleles of Kras and P53 in the murine pancreas. The first model was established through the pancreatic directed expression of a mutant KrasG12D allele and all mice developed pancreatic intraepithelial neoplasia (PanIN), a presumed precursor of PDA, before succumbing to invasive PDA at late ages. Mice with PanIN may be a suitable resource for developing biomarkers of early stage human pancreatic cancer, and evaluating potential chemoprevention strategies. The second model involved the pancreatic co-expression of endogenous mutant Kras and P53 alleles, which caused the early development of metastatic and lethal PDA. This model is particularly useful for the exploration of epithelial tumour metastasis, and for the evaluation of various therapeutic strategies.

Our efforts in melanoma involve the production of conditional endogenous alleles of mutant Braf, for targeted expression in melanocytes. We also participate in a clinical trial that uses a Braf inhibitor in patients with advanced melanoma.

Future projects

• Characterisation of the biochemical pathways involved in all stages of pancreatic neoplasia, particularly PanIN cell invasion, migration, survival and metastasis.
• Identification and functional analysis of the cell types that comprise PanINs and PDA.
• Evaluation of cytotoxic and targeted therapies for PanIN and PDA.
• Discovery of biomarkers of PanIN and PDA.
• Use of transposon mutagenesis to facilitate the evolution of PanIN to PDA.
• Establish a murine melanoma model.
• Clarify the role of oncogenic Kras and Braf in tumour initiation and maintenance.