Molecular Alterations that Reduce Cortical Containment of Tubulin Microtentacles and their Impact on Breast Tumor Metastasis

We find that the integrity of the cortical actin cytoskeleton is an important regulator of microtentacle formation, which can be mediated by genetic alteration of the cortactin protein that is commonly over-expressed in invasive breast cancers. Studies are underway to determine how these cortactin mutants influence the plasticity of detached tumor cells, using optical stretcher technology, and how these mechanical phenotypes translate to survival of circulating tumor cells in live animals. This genetic approach additionally led to the discovery of some interesting effects of cytoskeletally-targeted anti-mitotic chemotherapeutics, such as paclitaxel (Taxol). Studies of how these compounds affect cortical integrity and microtentacle formation revealed that although commonly used in clinical settings, very little was previously known about how acute exposures to these drugs impacts the behavior of suspended tumor cells. A manuscript was published on these studies by the PI, detailing how common anti-mitotic chemotherapeutics may inadvertently promote the survival of disseminated, chemotherapy-resistant tumor cells by impairing cortical integrity and enhancing microtentacle formation. Additionally, in vivo data now supports the initial hypothesis that MT-stabilizing chemotherapies can enhance circulating tumor cell binding and organ retention.