Molecular Mechanisms of Cancer Metastasis
A major focus of my research program involves identifying molecular mechanisms of cancer cell invasion that drive tumor metastasis. We study a family of adaptor proteins and protein-tyrosine kinases that have a common membrane targeting domain (Bin/Amphiphysin/Rvs or BAR). BAR proteins also have domains mediating protein-protein interactions (eg. SH2 or SH3), and some have additional enzymatic activities (eg FER/FES tyrosine kinases). In the past several years, we have played a leading role in defining the contributions of BAR proteins to cancer cell invasion and tumor metastasis. This includes BAR adaptor proteins that function in endocytosis of key receptors (eg. MT1-MMP) involved in cancer cells degrading surrounding extracellular matrix (ECM) in invasive protrusions called invadopodia (Hu et al. (2011) J Cell Sci). We have also recently identified a related adaptor protein (Toca-1) in promoting invadopodia formation in breast cancer cells, and showed that stable silencing of Toca-1 disrupts metastasis to lungs in mammary orthotopic xenograft models (Chander et al. (2013) Oncogene). Recent studies of the FES/FER tyrosine kinases in cancer by our group, have implicated FER in promoting metastasis in non-small cell lung cancer (Ahn et al. (2013) Mol Can Res), and FES in promoting breast tumor growth by promoting the recruitment of tumor-associated mast cells (Kwok et al. (2012) Mol Can Res). We are currently pursuing therapeutic approaches to extend on these largely genetic approaches used in these recent studies, in hopes of developing novel anti-metastasis therapies. To this end, we are actively collaborating with groups to test inhibitors of actin polymerization and MT1-MMP in cancer cell models of ECM degradation and cell invasion. We are also testing small molecule inhibitors of FES/FER tyrosine kinases and SHP2 protein-tyrosine phosphatase in metastatic cancer models. Our progress in the field of cancer cell invasion and metastasis was recently recognized with a Canadian Cancer Society Young Investigator award (May 2012), and featured on the covers of prestigious journals (J Cell Sci, Mol Can Res, Mol Cell Bio, Oncotarget). This research has been made possible by support from Canadian Institutes for Health Research (CIHR), Cancer Research Society (CRS), and Canadian Cancer Society Research Institute (CCSRI).