A Pro-Metastatic Secretory Program Activated By Epithelial-To-Mesenchymal Transition

Abstract Epithelial-to-mesenchymal transition (EMT) causes cancer cells to switch their axis of polarity from apical-basal to front-rear, which orients organelles and actin-based cytoskeletal structures in ways that facilitate purposeful cancer cell motility and metastasis1. Kurie lab reported that lung adenocarcinoma (LUAD) metastasis is EMT-dependent and that the EMT-activating transcription factor ZEB1 silences microRNAs that target key inhibitors of the polarity axis switch2-6. These data support the general belief that EMT-dependent metastasis is a cell-autonomous process. My new preliminary results, however, show that ZEB1 also activates the secretion of pro-metastatic effector proteins by initiating polarized trafficking of secretory vesicles toward the leading edge. These results, which build on findings that I made in the laboratory of Dr. Sandra Schmid7,8, underlie my hypothesis that ZEB1 initiates polarized secretion of pro-tumorigenic effector proteins to drive LUAD progression. We will test the hypothesis by completing the following specific aims.