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Andrew Ewald (Johns Hopkins), Cellular strategies and molecular mechanisms driving breast cancer metastasis
20 June 2023 | 17 h 00 min - 18 h 30 min
|Andrew J. Ewald, Ph.D.
Virginia DeAcetis Professor and Director, Department of Cell Biology
Director, Giovanis Institute for Translational Cell Biology
Johns Hopkins Medical School
Video of the event:
Cancer mortality is driven by metastasis, the process by which cells escape from the primary tumor and colonize distant organs. We have shown that luminal breast cancer cells can initiate invasion by expressing basal genes, such as keratin 14 (K14). K14+ luminal breast cancer cells collectively invade and intravasate as adherent clusters. Upon arrival at the distant site, K14+ clusters transition to K14- growing metastases. RNA-seq analysis revealed that K14+ cancer cells exhibit high expression of adhesion proteins (e.g. E-cadherin) and low expression of major histocompatibility complex class I (MHC I). We demonstrated genetically that E-cadherin represses invasion and promotes metastasis by acting as a survival factor. We next demonstrated that loss of MHC I expression sensitized K14+ cancer cells to natural killer (NK) cell attack and that cancer cells can induce NK cells to enter a novel metastasis-promoting cell state. We next tested how metastasis mechanisms differ in triple negative breast cancer (TNBC). We found that TNBC tumors express and require both epithelial and mesenchymal markers, as both E-cadherin and vimentin are required for metastasis. We are currently using genetic, multi-omic, and proteomic techniques to identify molecular regulators of metastatic cell states. We also develop and apply co-culture models to test the constraints imposed by intercellular interactions with both cancer and stromal cells.