TY - JOUR
T1 - EMT activates exocytotic Rabs to coordinate invasion and immunosuppression in lung cancer
AU - Xiao, Guan Yu
AU - Tan, Xiaochao
AU - Rodriguez, Bertha L.
AU - Gibbons, Don L.
AU - Wang, Shike
AU - Wu, Chao
AU - Liu, Xin
AU - Yu, Jiang
AU - Vasquez, Mayra E.
AU - Tran, Hai T.
AU - Xu, Jun
AU - Russell, William K.
AU - Haymaker, Cara
AU - Lee, Younghee
AU - Zhang, Jianjun
AU - Solis, Luisa
AU - Wistuba, Ignacio I.
AU - Kurie, Jonathan M.
N1 - Publisher Copyright:
Copyright © 2023 the Author(s).
PY - 2023/7/11
Y1 - 2023/7/11
N2 - 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.
AB - 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.
KW - epithelial-mesenchymal transition (EMT)
KW - lung cancer
KW - membrane trafficking
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U2 - 10.1073/pnas.2220276120
DO - 10.1073/pnas.2220276120
M3 - Article
C2 - 37406091
AN - SCOPUS:85163979189
SN - 0027-8424
VL - 120
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 28
M1 - e2220276120
ER -
