Martin McMahon, PhD

affiliated

Using genetically engineered mice we have generated new models of BRaf(V600E)-induced lung cancer and melanoma. We are using these mice to explore cancer initiation, progression and targeted therapy. We hypothesize that the initiating cells that give rise to lung tumors are likely to be bronchio-alveolar stem cells (BASCs). Similarly, we hypothesize that the initiating cells that give rise to melanoma are likely to melanoblasts, melanocyte stem cells that reside the bulge region of the hair follicle. We are currently designing experiments to test the importance of these cells in the tumor models that we have established. As a first step, we are developing conditions to allow us to isolate, culture and characterize both BASCs and melanoblasts. Initially, this characterization will comprise high throughput analysis of mRNA and miRNA expression patterns using a microarray approach. In addition, we are testing the effects of oncogenic BRaf(V600E) on the cell division cycle and apoptosis in the various stem cell populations. Next, we will test whether these are indeed tumor initiating cells by transplantation procedures as has been described for human cancers. Finally, we will test whether stem cells expressing oncogenic BRaf(V600E) are the source of tumor cells that re-grow following cessation of therapy targeted to the BRaf(V600E)-MEK-ERK MAP kinase pathway.