Abstract
Epithelial-to- mesenchymal transition (EMT) underlies immunosuppression, drug resistance, and metastasis in epithelial malignancies. However, the way in which EMT orchestrates disparate biological processes remains unclear. Here, we identify an EMT- activated vesicular trafficking network that coordinates promigratory focal adhesion dynamics with an immunosuppressive secretory program in lung adenocarcinoma (LUAD). The EMT-activating transcription factor ZEB1 drives exocytotic vesicular trafficking by relieving Rab6A, Rab8A, and guanine nucleotide exchange factors from miR-148a-dependent silencing, thereby facilitating MMP14-dependent focal adhesion turnover in LUAD cells and autotaxin-mediated CD8+ T cell exhaustion, indicating that cell- intrinsic and extrinsic processes are linked through a microRNA that coordinates vesicular trafficking networks. Blockade of ZEB1-dependent secretion reactivates antitumor immunity and negates resistance to PD-L1 immune checkpoint blockade, an important clinical problem in LUAD. Thus, EMT activates exocytotic Rabs to drive a secretory program that promotes invasion and immunosuppression in LUAD.
Document Type
Article
Publication Date
7-2023
Digital Object Identifier (DOI)
https://doi.org/10.1073/pnas.2220276120
Funding Information
This work was supported by the (NIH) through R01 CA181184 (to J.M.K.), R01 CA2111125 (to J.M.K.), K99 CA249048 (to G.-Y.X), NIH Lung Cancer SPORE grant P50 CA70907 (to J.M.K.) and by CPRIT-MIRA RP160652. J.M.K. holds the Gloria Lupton Tennison Distinguished Professorship in Lung Cancer. The work was also supported by the generous philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shots Program, the Gil and Dody Weaver Foundation and Bill and Katie Weaver Charitable Trust, and the MD Anderson Cancer Center Support Grant P30 CA016672. This study was supported by the Translational Molecular Pathology-Immunoprofiling Moonshots Platform (TMP-IL) at the Department of Translational Molecular Pathology, the University of Texas MD Anderson Cancer Center.
Repository Citation
Xiao, Guan-Yu; Tan, Xiaochao; Rodriguez, Bertha L.; Gibbons, Don L.; Wang, Shike; Wu, Chao; Liu, Xin; Yu, Jiang; Vasquez, Mayra E.; Tran, Hai T.; Xu, Jun; Russell, William K.; Haymaker, Cara; Lee, Younghee; Zhang, Jianjun; Solis, Luisa; Wistuba, Ignacio I.; and Kurie, Jonathan M., "EMT activates exocytotic Rabs to coordinate invasion and immunosuppression in lung cancer" (2023). Markey Cancer Center Faculty Publications. 329.
https://uknowledge.uky.edu/markey_facpub/329
Notes/Citation Information
Copyright © 2023 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial- NoDerivatives License 4.0 (CC BY-NC- ND).