Event Information

BIOE Seminar: Cancer Cell & Immune Cell State Dynamics during Breast Cancer Metastasis
Friday, November 5, 2021
9:00 a.m.-10:00 a.m.
A. James Clark Hall, Room 2121
For More Information:
Dr. Kim Stroka

Dr. Andrew Ewald
Director, Department of Cell Biology
Professor of Cell Biology
Johns Hopkins University

*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
Dr. Ewald earned his B.S. in Physics from Haverford College and his Ph.D. in Biochemistry and Molecular Biophysics from Caltech, then completed postdoctoral training at UCSF.  He started his own lab at Johns Hopkins in 2008. He is now Professor and Director of Cell Biology in the Johns Hopkins University, School of Medicine, Professor of Biomedical Engineering, and Professor of Oncology and Co-Leader of the Cancer Invasion and Metastasis Program in the Sidney Kimmel Comprehensive Cancer Center. Dr. Ewald is internationally recognized for his research on the molecular mechanisms of cancer invasion and metastasis, has given over 100 invited talks and received awards from diverse societies and foundations.  His research has been funded by the National Cancer Institute, the National Science Foundation, the Department of Defense, the JKTG Foundation, the METAvivor Foundation, and the Breast Cancer Research Foundation.



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