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

2 Scopus citations

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.

Original languageEnglish (US)
Article numbere2220276120
JournalProceedings of the National Academy of Sciences of the United States of America
Volume120
Issue number28
DOIs
StatePublished - Jul 11 2023
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'EMT activates exocytotic Rabs to coordinate invasion and immunosuppression in lung cancer'. Together they form a unique fingerprint.

Cite this