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. As a graduate student in Scott Fraser’s Lab at Caltech he utilized his physics training to develop and apply novel light microscopy approaches to reveal cellular interactions within intact tissues in real-time. During Dr. Ewald’s postdoctoral studies in Zena Werb’s Lab at UCSF, he developed novel 3D organotypic culture and imaging techniques to reveal the cellular mechanisms and molecular regulation of morphogenesis in primary normal and neoplastic mammary epithelia. 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.
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. Dev Cell. 2018 PubMed PMID: 29634937.
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. Proc Natl Acad Sci U S A. 2016 PMID: 26831077.
Ellison D, Mugler A, Brennan MD, Lee SH, Huebner RJ, Shamir ER, Woo LA, Kim J, Amar P, Nemenman I, Ewald AJ, Levchenko A. Cell-cell communication enhances the capacity of cell ensembles to sense shallow gradients during morphogenesis. Proc Natl Acad Sci U S A. 2016 PMID: 26792522.
Shamir ER, Pappalardo E, Jorgens DM, Coutinho K, Tsai WT, Aziz K, Auer M, Tran PT, Bader JS, Ewald AJ. Twist1-induced dissemination preserves epithelial identity and requires E-cadherin. J Cell Biol. 2014 PMID: 24590176.
Cheung KJ, Gabrielson E, Werb Z, Ewald AJ. Collective invasion in breast cancer requires a conserved basal epithelial program. Cell. 2013 PMID: 24332913.