Virginia DeAcetis Professor in Basic Cancer Research
Professor and Director, Cell Biology Department, Johns Hopkins School of Medicine
Co-Leader, Cancer Invasion and Metastasis Program, Sidney Kimmel Comprehensive Cancer Center
RESEARCH OVERVIEW
Dr. Ewald has spent the past decade developing imaging, genetic, and 3D organotypic culture techniques to enable real-time analysis of cell behavior and molecular function in breast cancer. His laboratory seeks to understand how epithelial cancer cells escape their normal developmental constraints and acquire the ability to invade and disseminate into normal tissues.
Invasion is a fundamental step in breast cancer progression and a driving force for metastasis. However, the relative contribution of different epithelial cancer cell subpopulations to invasion and metastasis remains unclear. Dr. Ewald and colleagues developed a novel series of assays to identify the most invasive cancers cells in primary tumors from genetically engineered mouse models of breast cancer and in primary human breast tumors. They identified a common molecular phenotype in the invasive leader cells (K14+) across mouse models of luminal B, Her2+, and basal breast cancer and in patient tumor samples from multiple subtypes of breast cancer. These K14+ cells led invasion in 3D culture and led collective invasion into normal tissue in vivo. In the luminal B model, the invasive molecular program was expressed in ~2% of primary cancer cells but 90% of lung metastases. Furthermore, genetic knockdown of this basal molecular program (shRNA against p63 or K14) was sufficient to limit invasion of all of the cancer cells. His work establishes a new paradigm for collective cell invasion and identifies a common molecular biology regulating invasive behavior across models of distinct subtypes of breast cancer.
Cancer Biology | Cell Biology | Genetics, Genomics and Gene Regulation | Translational Research
Selected Publications
Chan IS, Knútsdóttir H, Ramakrishnan G, Padmanaban V, Warrier M, Ramirez JC, Dunworth M, Zhang H, Jaffee EM, Bader JS, Ewald AJ. Cancer cells educate natural killer cells to a metastasis-promoting cell state. Journal of Cell Biology, 2020.
Padmanaban V, Krol I, Suhail Y, Szczerba BM, Aceto N, Bader JS, Ewald AJ. E-cadherin is required for metastasis in multiple models of breast cancer. Nature, 2019.
Neumann NM, Perrone MC, Veldhuis JH, Huebner RJ, Zhan H, Devreotes PN, Brodland GW, Ewald AJ. Coordination of Receptor Tyrosine Kinase Signaling and Interfacial Tension Dynamics Drives Radial Intercalation and Tube Elongation. Developmental Cell, 2018.
Cheung KJ, Padmanaban V, Silvestri V, Schipper K, Cohen JD, Fairchild AN, Gorin MA, Verdone JE, Pienta KJ, Bader JS, Ewald AJ. Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters. PNAS, 2016.
Cheung KJ, Gabrielson E, Werb Z, Ewald AJ. Collective invasion in breast cancer requires a conserved basal epithelial program. Cell, 2013.
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