Hannah Carter, PhD, Professor of Medicine at UCSD, in collaboration with Drs. Prashant Mali and Stephanie Fraley.
"In vivo high throughput screening to identify protein interactions required for breast cancer metastasis"
Significance: Metastasis accounts for ~90% of breast cancer related deaths1. Despite the advent of effective immunotherapies in the past decade, most patients with advanced-stage and/or high-risk cancers continue to die due to metastatic disease or complications of its treatment2. Cancer cell migration is essential for metastasis, and experts have suggested that targeting migration to prevent initial metastasis and secondary spread will be the most effective strategy for reducing cancer mortality34. However, “a paucity of preclinical discovery and thus clinical development exists for agents targeting the biological mechanisms underlying the metastatic process.5” This proposal focuses on elucidating the molecular networks underlying metastatic breast cancer cell migration in vivo. The successful completion of this study will identify and validate critical molecular regulators of metastasis, which will inform therapeutic strategies to prevent or halt breast cancer progression. A novel approach for cancer treatment is to specifically target metastatic cells that migrate away from the primary tumor and enter the bloodstream, preventing their spread to other organs. To develop such a therapy, it is necessary to first characterize the molecular networks driving a cancer cell to migrate and enabling them to enter the vasculature. This project will explore a newly discovered migration behavior used by cancer cells to spread collectively, instead of as individual cells. This behavior is thought to facilitate the survival of cancer cells outside of the tumor environment and enable efficient metastatic spread. However, little is known about what causes this behavior or which molecules could be targeted to prevent or halt it. The Fraley lab has discovered how the environment surrounding tumor cells can trigger this collective migration behavior and has identified a set of proteins involved in this process6,7.The Mali lab has developed a technique, PepTile8, that enables probing protein regions associated with function as opposed to whole gene knockout, which while commonly used for functional assays, cannot distinguish between specific protein activities in a functional context. The goal of this project is to leverage these two advances to identify proteins and protein-interactions required for collective cancer cell migration and metastasis and assess their potential as therapeutic targets to stop metastasis. The resulting information will be used in future translational studies to develop strategies for therapy that can limit metastasis and improve patient outcomes.
Innovation: Our study combines expertise in molecular screening assay development (Mali), murine models of breast cancer cell migration and metastasis (Fraley) and computational analysis of protein function in cancer (Carter) to systematically uncover protein interactions that are targetable dependencies required for breast cancer cell metastasis. This entails the following innovations:
