Abstract 673: The EMT activator ZEB1 initiates polarized secretion of pro-tumorigenic effector proteins to drive lung adenocarcinoma progression

Abstract There are few effective therapeutic options for metastatic lung adenocarcinomas (LUADs) that lack actionable mutations in receptor tyrosine kinases, and there is an urgent need to develop a better understanding of the biological basis of LUAD growth and metastasis. Our group has developed mouse models of LUAD metastasis and found that LUAD metastasis is epithelial-to-mesenchymal transition (EMT)-dependent. EMT causes cancer cells to switch their axis of polarity from apical-basal to front-rear, which orients organelles and actinbased cytoskeletal structures in ways that facilitate purposeful cancer cell motility and metastasis. The EMT-activating transcription factor ZEB1 silences microRNAs that target key inhibitors of the polarity axis switch. These data support the general belief that EMT-dependent metastasis is a cell-autonomous process. However, our new findings here show that ZEB1 coordinates the components of secretory trafficking machinery, Rab6A and Rab8A, via silencing miR-148a that target these effectors, to drive polarized secretory trafficking toward the leading edge of LUAD cells, to enhance surface exposure of MMP14 so that triggers ECM degradation, accelerates focal adhesion turnover and promotes cancer cell migration. Moreover, the ZEB1-driven secretory trafficking increases the secretions of cytokines and immunomodulation factors, to generate an immunosuppressive tumor microenvironment, and to promote LUAD metastasis. These findings advance a paradigm in which EMT drives LUAD metastasis through a cell non-autonomous mechanism. The novelty rests in our results that demonstrate a transcriptional governance of polarized vesicular transport, providing the potential to target ZEB1-driven secretory pathways for the purpose of blocking metastasis in LUAD. Citation Format: Guan-Yu Xiao, Xiaochao Tan, Leticia Rodriguez, Xin Liu, Jiang Yu, Mayra Vasquez, Hai Tran, William Russell, Don Gibbons, Jonathan Kurie. The EMT activator ZEB1 initiates polarized secretion of pro-tumorigenic effector proteins to drive lung adenocarcinoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 673.