EMT activates exocytotic Rabs to coordinate invasion and immunosuppression in lung cancer

Guan Yu Xiao, Xiaochao Tan, Bertha L. Rodriguez, Don L. Gibbons, Shike Wang, Chao Wu, Xin Liu, Jiang Yu, Mayra E. Vasquez, Hai T. Tran, Jun Xu, William K. Russell, Cara Haymaker, Younghee Lee, Jianjun Zhang, Luisa Solis, Ignacio I. Wistuba, Jonathan M. Kurie

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article numbere2220276120
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number28
StatePublished - Jul 11 2023

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. 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.

Publisher Copyright:
Copyright © 2023 the Author(s).


  • epithelial-mesenchymal transition (EMT)
  • lung cancer
  • membrane trafficking

ASJC Scopus subject areas

  • General


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