Andrew Ewald, PhD

Understanding how breast cancer spreads and identifying preventive strategies to improve patient outcomes.

Impact

The major cause of breast cancer deaths is metastasis, the process by which breast cancer cells invade distant organs and establish new tumors there. To prevent this process from occurring, researchers must first identify the mechanisms that drive it. Dr. Ewald is studying metastasis at the cellular and molecular level with the goal of discovering ways to both prevent and treat metastatic breast cancer (MBC). His findings may guide the development of new strategies to improve outcomes for women with MBC.

Progress Thus Far

Metastasis requires cancer cells to accomplish many different tasks: escaping the primary tumor, entering, and surviving within blood vessels, evading immune cells, and growing in an unfamiliar organ. To succeed, cancer cells must first break free from the tumor and then they must survive as they travel through the body. The main lesson Dr. Ewald has learned from his BCRF-funded research is that the most dangerous cancer cells are the ones that are the most flexible—those that can rapidly change their structure and function to accomplish each successive task in metastasis.

Dr. Ewald and his team have uncovered the roles of proteins in two molecular complexes that maintain tissue connectivity: the tight junction and the adherens junction. Both structures enable strong connections among cells but have very different roles. The protein Claudin 7 in the tight junction is a natural defense against metastasis and its loss makes cancer cells more metastatic, while loss of the key protein of the adherens junction, E-cadherin, surprisingly made cancer cells less metastatic because the cancer cells rapidly died. The team demonstrated that this is because half of E-cadherin mediates adhesion and suppresses invasion while the other half promotes cell survival. The different halves can play different roles because specific enzymes can cleave the protein into different pieces that function in different parts of the cell. These discoveries may represent new strategies to target the molecular pathways driving metastasis.

What’s next

In the coming year, Dr. Ewald will utilize genetic and molecular techniques to identify exactly which parts of E-cadherin accomplish these different functions and where they occur within the cancer cells. Together, these experiments will define the molecular interactions among cancer cells that alternatively resist and promote metastasis. Dr. Ewald’s goal is to apply these insights to target the molecular vulnerabilities of metastatic breast cancer cells.