The Yin and Yang of Cancer Metastasis

Metastatic dissemination of cancer cells from the primary tumor and their spread to distant sites in the body is the leading cause of mortality in breast cancer patients. Invasive cancer cells penetrate through the basement membrane and into blood vessels using invadopodia, F-actin rich protrusions with matrix-degrading activity. Focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (Pyk2) define a distinct family of non-receptor tyrosine kinases that are highly expressed in invasive cancers, but the molecular mechanism by which these proteins regulate invasiveness of breast cancer cells to neighboring tissues and their subsequent metastatic dissemination is largely unknown.

Using high-throughput protein array screening followed by bioinformatics analysis, we identified cortactin as a novel substrate and interactor of Pyk2 in invadopodia. Pyk2 colocalizes with cortactin to invadopodia of invasive breast cancer cells, where it mediates epidermal growth factor-induced cortactin tyrosine phosphorylation both directly and indirectly via Src-mediated Abl-related gene (Arg) activation, leading to actin polymerization in invadopodia, extracellular matrix degradation, and tumor cell invasion. Further in vivo cancer metastasis assays and high-resolution intravital imaging revealed that both Pyk2 and FAK regulate tumor cell invasion and consequent in vivo metastatic dissemination, but that they do so via distinct and complementary motility mechanisms. These observations were validated by detailed proteogenomics and network analyses, which revealed the in vivo molecular mechanisms and signaling pathways by which FAK family proteins coordinate the regulation of breast cancer motility and invasion. Our data present FAK family kinases as a novel target for inhibition of breast cancer metastasis.