Research Topic
1) Mechanisms driving growth and development of normal epithelial cells; 2) Cellular strategies driving cancer invasion and metastasis; 3) Regulation of cancer progression by the tumor microenvironment

Background and Summary
The Ewald Lab seeks to understand how groups of cells cooperate, compete, and interact to organize tissue architecture and function during development and disease progression. Our foundation is the understanding of normal organ architecture and development: how are they built during early development and then remodeled during adult life? Our disease focus is on breast cancer and, specifically, on elucidating the cellular strategies and molecular mechanisms driving metastasis. Metastasis is the multistep process by which cancer cells acquire the ability to leave the primary tumor, travel through the circulation, evade the immune system, and establish new tumors in distant vital organs. More than 90% of cancer deaths are attributable to metastasis across all organ sites. Unfortunately, few approved drugs specifically target the metastatic process, and current therapies are insufficiently effective for patients with metastatic cancer.

Our Conceptual and Experimental Approach
Cancer is the #2 cause of death in the United States and more than 90% of cancer deaths occur at metastatic stages. Yet, it is also understudied and incompletely understood. How can this be? Why isn’t metastasis already mechanistically understood and efficiently targeted by modern medical therapies? There are three fundamental challenges to studying metastasis: the essential processes occur deep inside the body, over a time period of months to decades, and it is an inherently complex systems problem. The experimental inaccessibility and long duration of metastasis makes it relatively inaccessible to microscopic observation or experimental manipulation, the basic tools of modern biology. The complexity arises because cells with organs live a social life- surrounded by and mutually influencing a diverse range of other cell types and responsive to the mechanical and chemical signals around them. Complexity hits twice- it makes it difficult to know where to start and also makes the field of metastasis unappealing to scientists who only engage with simple problems.

We recognized that major progress in understanding and treating metastatic cancer would require fundamentally new experimental tools and research ecosystems. We therefore developed new approaches that allowed us to culture live tumor tissue in the laboratory. We grow cancer cells in three dimensional (3D) environments customized to model specific stages in cancer progression, including tumor initiation, tumor growth, cancer invasion, entry into blood vessels, immune evasion, and growth of metastases in distant organs. Recent advances in laboratory automation and image analysis enable us to conduct these experiments at a large scale in a short time period, for example testing the effect of 1,000 drugs on metastasis initiation within a week. We combine cutting-edge microscopy, advanced genetics, next-generation bulk and single cell sequencing, and bioinformatic analysis to: understand how cells accomplish specific steps in metastasis, define the molecular tool-kit they utilize, and identify targets for new anti-metastatic drugs.

Research Ecosystem
Metastasis is a complex systems problem with key changes occurring at level of molecules, cells, tissues, organs, and whole-body physiology. Accordingly, it first requires the successful integration of diverse biological expertise that is normally siloed in different departments. Second, it requires the combination of deep knowledge of biological systems with the experimental, analytical, and computational frameworks developed in math, physics, and engineering. Third, it requires a fusion of the academic understanding of disease processes and the clinical and patient realities that cancer develops in real human beings, with sometimes hopeful and other times tragic consequences. Dr. Ewald earned his B.S. in physics at Haverford College and his Ph.D. in Biochemistry and Molecular Biophysics at Caltech, then did postdoctoral training at UCSF in epithelial biology and cancer metastasis. This multidisciplinary background enables him to assemble and lead teams of scientists, engineers, and clinicians to understand this terrible disease. To increase our impact within breast cancer and extend to additional cancer types, Dr. Ewald founded the Cancer Invasion and Metastasis Research Program (CIM) within the Sidney Kimmel Comprehensive Cancer Center (SKCCC). CIM brings together >40 faculty from the School of Medicine, Bloomberg School of Public Health, and the Whiting School of Engineering. CIM is co-led by Dr. Ewald, Dr. Ashani Weeraratna, and Dr. Phuoc Tran with the shared goal of understanding the biological processes driving metastasis and translating these insights to clinical trials to improve patient outcomes. The final critical piece of this ecosystem is active collaboration with the National Cancer Institute (NCI), with cancer patient advocates, and with research foundations, including BCRF, Twisted Pink, Hope Scarves, METAvivor, and the JKTG Foundation for Health and Policy. Our interactions with patient advocates provide inspiration and scientific direction for our research and critical funding for high risk, high reward projects. Partnership with the NCI, particularly through the CTD2 and PSOC Networks, provides stable, long-term funding and facilitates collaborations with leading researchers across the country.

Areas of Current Research Focus
The Ewald Lab is organized to answer three fundamental questions: