Andrew Ewald, PhD
Assistant Professor, Departments of Cell Biology and Oncology
Member, Center for Cell Dynamics
Member, Breast Cancer Program
Sidney Kimmel Comprehensive Cancer Center
Johns Hopkins University School of Medicine
2013-2014 BCRF Project:
The overwhelming majority of breast cancer mortality is caused by metastasis. Dr. Ewald seeks to improve outcomes for patients by developing therapeutic strategies to target metastatic progression directly. Most drug development assays model proliferation but not metastasis-specific cell behaviors such as invasion, dissemination, and formation of secondary metastatic sites. The majority of current breast cancer therapies function by blocking proliferation or by eliminating rapidly dividing cells. Unfortunately, these therapies have limited efficacy in metastatic breast cancer patients. Dr. Ewald’s global hypothesis is that molecular insight into metastasis-specific cell behaviors will enable identification of metastasis targeted therapeutic strategies.
Dr. Ewald’s research started from a very simple question: which cells in a breast tumor are the most dangerous to the health of the patient? To answer this question, his group developed novel 3D culture assays to model the early steps of metastasis. Their methods enable them to force the cancer cells to run a sophisticated 3D “race” and they classify the cells at the front as the “invasive leaders.” Surprisingly, Dr. Ewald and colleagues discovered that cells with a basal epithelial phenotype led collective invasion within live 3D cultures of model and human tumors. Their work revealed a common molecular biology regulating invasive behavior across models of distinct subtypes of breast cancer. Dr. Ewald’s team then used molecular interference techniques to demonstrate that these basal genes are required for breast cancer invasion. In 2013-2014, they will leverage their basic science insights to develop therapeutic strategies to inhibit metastatic progression in patients. Their data provide a rationale and a strategy for targeting metastasis-specific cell behaviors. Their approach is novel and independent of existing proliferation-targeted drugs. Accordingly, Dr. Ewald’s group anticipates that invasion-targeted agents will synergize with existing drugs and benefit metastatic breast cancer patients.
Metastasis is the process by which cancer cells leave the original tumor, migrate, and colonize distant organs in the body, and it is the major cause of death from breast cancer. Dr. Ewald’s research focus is to understand the molecular basis of metastatic spread with the goal of developing strategies to improve outcomes for patients with metastatic breast cancer. In the past year his team discovered that a set of "basal" epithelial genes are expressed specifically in the cancer cells that lead the invasion into normal tissues. Importantly, the "leader cells" express these basal genes during invasion in breast tumors from patients with luminal A, luminal B, and triple negative breast cancer. When the researchers turned off these basal genes, breast tumors were no longer able to invade. Their research now focuses on developing innovative therapies that target molecules in these newly discovered invasive leader cells with the goal of turning metastatic breast cancer into a managed chronic disease. BCRF support is critical to our efforts.
Dr. Andrew Ewald received his doctorate in Biophysics & Embryology from the California Institute of Technology and completed a post-doctoral fellowship at the University of California, San Francisco (UCSF). He 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 at Caltech, Dr. Ewald utilized his physics training to develop and apply novel light microscopy approaches to reveal cellular interactions within intact tissues in real-time. During his postdoctoral studies 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 laboratory models of breast cancer and in primary human breast tumors. They identified a common molecular phenotype in the invasive leader cells (K14+) across laboratory models of luminal B, HER2+, and basal breast cancer and in patient tumor samples from multiple subtypes of breast cancer. Dr. Ewald’s work aims to establish a new paradigm for collective cell invasion and identifies a common molecular biology regulating invasive behavior across models of distinct subtypes of breast cancer.