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

doi:10.1073/pnas.2220276120

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 journal › Article › peer-review

1 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 language	English (US)
Article number	e2220276120
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	120
Issue number	28
DOIs	https://doi.org/10.1073/pnas.2220276120
State	Published - Jul 11 2023

Keywords

epithelial-mesenchymal transition (EMT)
lung cancer
membrane trafficking

ASJC Scopus subject areas

General

MD Anderson CCSG core facilities

Research Animal Support Facility

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10.1073/pnas.2220276120

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Xiao, G. Y., Tan, X., Rodriguez, B. L., Gibbons, D. L., Wang, S., Wu, C., Liu, X., Yu, J., Vasquez, M. E., Tran, H. T., Xu, J., Russell, W. K., Haymaker, C., Lee, Y., Zhang, J., Solis, L., Wistuba, I. I., & Kurie, J. M. (2023). EMT activates exocytotic Rabs to coordinate invasion and immunosuppression in lung cancer. Proceedings of the National Academy of Sciences of the United States of America, 120(28), Article e2220276120. https://doi.org/10.1073/pnas.2220276120

Xiao, GY, Tan, X, Rodriguez, BL , Gibbons, DL , Wang, S , Wu, C, Liu, X, Yu, J, Vasquez, ME, Tran, HT, Xu, J, Russell, WK, Haymaker, C , Lee, Y , Zhang, J , Solis, L , Wistuba, II & Kurie, JM 2023, 'EMT activates exocytotic Rabs to coordinate invasion and immunosuppression in lung cancer', Proceedings of the National Academy of Sciences of the United States of America, vol. 120, no. 28, e2220276120. https://doi.org/10.1073/pnas.2220276120

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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.",

keywords = "epithelial-mesenchymal transition (EMT), lung cancer, membrane trafficking",

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

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doi = "10.1073/pnas.2220276120",

language = "English (US)",

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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.

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)

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KW - membrane trafficking

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ER -

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

Abstract

Keywords

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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