Abstract IA17: Collective epithelial routes to metastatic spread

Abstract

Abstract The spread of cancer to distant organs is the major driver of mortality in cancer and, unfortunately, few therapies are effective in patients with extensive metastatic disease. Our hypothesis is that deeper mechanistic insight into the biological basis of metastasis will lead to novel therapeutic concepts. We have focused our laboratory investigations on understanding how epithelial cells acquire the ability to release their connections with their neighbors, migrate through the stroma, and enter the systemic circulation. The prevailing model when we began was the epithelial to mesenchymal transition (EMT), which posited a loss of epithelial features in the cancer cells during metastasis. The EMT model was controversial, in part because metastatic tumors typically retain many epithelial features. However, it remained possible that epithelial features were lost during stages of transit that are difficult to impossible to observe in vivo. To distinguish these possibilities, we developed novel 3D organoid assays to model normal epithelial growth, to determine the molecular requirements for Twist1 induced dissemination and to identify molecular programs driving the colonization of distant organs. The conclusions drawn across these studies are (1) that there are normal epithelial migratory programs that can be rapidly co-opted through activation of RTK signaling, (2) that the epithelial cell adhesion machinery can facilitate dissemination, and (3) that clusters of breast cancer cells utilize epithelial-specific gene expression (e.g. keratin-14) as they invade, disseminate, and colonize distant organs. These insights lead us to view metastasis as a process that can be accomplished without loss of epithelial character and that these epithelial routes to metastasis may have unique vulnerabilities compared to EMT models. We will discuss the latest progress in these studies and also technical advances in 3D culture that will accelerate metastasis research across organ sites. Citation Format: Andrew J. Ewald. Collective epithelial routes to metastatic spread. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr IA17.