| Event Information
BIOE Seminar: Cancer Cell & Immune Cell State Dynamics during Breast Cancer Metastasis
Dr. Andrew Ewald
*BGSS Students' Choice Seminar*
Cancer cell and immune cell state dynamics during breast cancer metastasis
The majority of cancer mortality is attributable to metastasis, the process by which cells escape from the primary tumor, access the systemic circulation, and colonize distant organs. Our recent work demonstrated that metastasis can be accomplished by cancer cells that retain an epithelial phenotype, while transitioning between distinct phenotypic states specialized for either proliferation or migration. We showed that proliferative breast cancer cells acquire migratory and invasive potential through the expression of basal genes, such as keratin 14 (K14) and p63. This transition occurs specifically at the tumor stroma border. These K14+ cancer cells collectively invade and intravasate as adherent groups of cells, through microenvironments defined by aligned, fibrillar collagen I. Upon arrival at the distant site, these predominantly K14+ clusters transition to predominantly K14- growing metastases. RNA-seq analysis revealed that K14+ breast cancer cells exhibited higher expression of diverse cell-cell and cell-matrix adhesion receptors (e.g. E-cadherin) and lower expression of the major histocompatibility complex class I (MHC I). We then used genetic approaches to show that E-cadherin represses invasion and promotes metastasis by acting as a survival factor for cancer cells during systemic dissemination and early seeding. The molecular mechanism is by limiting TGF-beta dependent reactive oxygen species accumulation. We next demonstrated that loss of MHC I expression sensitized K14+ cancer cells to natural killer (NK) cell attack and that this effect was limited as NK cells lost their cytotoxic effects within days of contact with cancer cells, instead converting to a novel metastasis-promoting cell state. Mechanistically, NK cell reprogramming depended on the TIGIT and Klrg1 receptors and on DNA methyltransferases. We are currently working to test the limits of this emerging “collective epithelial metastasis” model in the context of triple negative breast cancer. Our ultimate goal is to develop novel concepts for anti-metastatic therapies.
About the Speaker