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

30 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
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

Bibliographical note

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

Funding

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.

Funders	Funder number
CPRIT-MIRA	RP160652
Gil and Dody Weaver Foundation
National Institutes of Health (NIH)	P50 CA70907, R01 CA2111125, K99 CA249048, R01 CA181184
University of Texas Anderson Cancer Center	P30 CA016672
Bill and Katie Weaver Charitable Trust

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

epithelial-mesenchymal transition (EMT)
lung cancer
membrane trafficking

ASJC Scopus subject areas

General

Access to Document

10.1073/pnas.2220276120

Cite this

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

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title = "EMT activates exocytotic Rabs to coordinate invasion and immunosuppression in lung cancer",

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.\}",

note = "Publisher Copyright: Copyright {\textcopyright} 2023 the Author(s).",

year = "2023",

month = jul,

day = "11",

doi = "10.1073/pnas.2220276120",

language = "English",

volume = "120",

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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

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.

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

UR - https://www.scopus.com/pages/publications/85163979189

UR - https://www.scopus.com/pages/publications/85163979189#tab=citedBy

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 -

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

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

ASJC Scopus subject areas

Access to Document

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