Determining the roles of membrane tension in breast cancer cell migration

Abstract

Within the past two years, breast cancer has exceeded lung cancer as the most frequently diagnosed cancer, ranking first for incidence and mortality in most of the world. Cancer reaches its deadliest stage when metastatic spread of cells occurs from tumor sites. Cell metastasis relies, in part, on 1) endocytic membrane trafficking and 2) the formation of adhesive contacts with the extracellular matrix. These processes are regulated by mechanical tension on the cell membrane, which varies spatially within migrating cells. While tension gradients assist in maintaining polarity of the cell during migration, recently it has been shown that these gradients create an asymmetry in endocytic dynamics across the plasma membrane, termed as polarized membrane trafficking. Our preliminary data have shown that changes in membrane tension additionally result in the heterogeneous expression of two distinct adhesive structures during proliferation and nondirectional migration of breast cancer cells. Although membrane tension, endocytosis, adhesion, and cell migration have been extensively studied individually, it is unknown how these processes are collectively regulated by breast cancer cells to metastasize. We thus aim to develop experimental and analytical approaches that will allow us to monitor polarized membrane trafficking, the formation of adhesive structures, and membrane tension in several migrating breast epithelial cell lines. This involves using a microfluidic platform that simultaneously allows the leading and trailing edge of a cell to be separately treated during migration and enables the application of inputs native to the cellular microenvironment. Examination of the various regulatory pathways on the cell membrane that contribute to breast cancer metastasis will significantly impact the development of therapeutic targets in breast cancer drug discovery.