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

Author:

Xiao Guan-Yu1ORCID,Tan Xiaochao1ORCID,Rodriguez Bertha L.1,Gibbons Don L.1,Wang Shike1,Wu Chao1,Liu Xin1,Yu Jiang1,Vasquez Mayra E.1,Tran Hai T.12ORCID,Xu Jun3,Russell William K.4ORCID,Haymaker Cara5ORCID,Lee Younghee5,Zhang Jianjun1ORCID,Solis Luisa5,Wistuba Ignacio I.5,Kurie Jonathan M.1

Affiliation:

1. Department of Thoracic/Head and Neck Medical Oncology, The University of Texas Monroe Dunaway (MD) Anderson Cancer Center, Houston, TX 77030

2. Division of Cancer Medicine, The University of Texas Monroe Dunaway (MD) Anderson Cancer Center, Houston, TX 77030

3. Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030

4. Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555

5. Department of Translational Molecular Pathology, The University of Texas Monroe Dunaway (MD) Anderson Cancer Center, Houston, TX 77030

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.

Funder

HHS | NIH | National Cancer Institute

Cancer Prevention and Research Institute of Texas

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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