BBB Seminar: David Micklem
Functional genetic discovery of an essential role for Axl in breast cancer metastasis
Metastasis underlies the majority of cancer-related deaths, so furthering our understanding of the molecular mechanisms that enable tumor cell dissemination is a vital health issue. I will outline the experimental models that the Lorens lab have developed and used to identify the receptor tyrosine kinase Axl as an important player in mammary tumor cell invasion and metastasis. The expression of Axl in breast cancer predicts strongly reduced overall patient survival. Using a novel epi-allelic RNA interference analysis strategy in metastatic breast cancer cells we delineated a distinct threshold of Axl expression required for mesenchymal-like in vitro cell invasiveness. Using a new in vivo imaging reporter system we generated breast carcinoma cell lines for optical imaging and monitored experimental breast tumor growth in tissue engineered microenvironments in vivo. By in vivo epi-allelic analysis we titrated the requisite Axl expression level for growth in foreign microenvironments. We further developed human and syngenic mouse optical imaging-compatible experimental breast cancer metastasis models to allow non-invasive kinetic monitoring of breast cancer spread from the mammary gland. Importantly, we demonstrated that Axl knockdown completely prevented the spread of highly metastatic breast carcinoma cells from the mammary gland to lymph nodes and major organs, and increased overall survival. As a highly 'druggable' protein Axl represents a promising new target for developing anti-cancer therapeutics.
Chair: Stein Ove Døskeland, Department of Biomedicine