Exploration of the dynamics of E-selectin interaction in breast cancer metastasis

Princeton University, Princeton NJ

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Abstract

? DESCRIPTION (provided by applicant): Since the identification of specific molecular profiles which mediate breast cancer metastasis to the lung, bone and brain, considerable attention has been focused on discerning how these molecular traits influence a tumor cell's interactions with the host stroma. Specifically, we are interested in interactions that impact the dissemination and progression of metastatic cancers. Inter-cellular adhesion molecules have been the focus of many of these studies as they provide the first means of direct communication between metastasizing cells and the vasculature of distant organs. Among these adhesion molecules, E-selectin is a well-characterized receptor expressed by the host endothelial cells which is thought to capture metastatic cells during the initial stages of metastasis. Despite many studies which support a mechanism for early seeding in vitro, in vivo evidence for the pro-metastatic role for E-selectin is still inconsistent. This project seeks to understand the dynamics of E-selectin binding during cancer metastasis, and will investigate a novel role for E-selectin in promoting metastatic progression. The effects of E-selectin ablation on breast cancer metastasis will be analyzed through mouse models, and the effects of E-selectin on tumor progression will be analyzed with state-of-the-art imaging and histology methods. Finally, important genetic elements responsible for the generation of E-selectin ligands and their clinical relevance will be investigated. Overall this project will revisit the role of E-selectin in metastasis, and shed light on the potential for therapeutic targeting of the E-selectin- dependent pro-metastatic pathway. It will also define the specific molecular traits which lead to poor prognosis of cancer patients, and may lead to an enhanced ability to stratify patients on the basis of metastatic risk.