biostudies-literatureXiao GYHHS | NIH | National Cancer InstituteNCI NIH HHSCancer Prevention and Research Institute of Texase2220276120https://www.ebi.ac.uk/biostudies/studies/S-EPMC10334751biostudies-literatureUnknown120(28)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 linkProceedings of the National Academy of Sciences of the United States of AmericaEMT activates exocytotic Rabs to coordinate invasion and immunosuppression in lung cancer.PMC10334751R00 CA249048P50 CA070907P30 CA016672P50 CA70907R01 CA236781R01 CA2111125R01 CA211125RP160652K99 CA249048R01 CA181184Haymaker CGibbons DLZhang JWistuba IIXiao GYWu CRodriguez BLYu JXu JRussell WKLiu XKurie JMTan XSolis LWang SVasquez MELee YTran HTfalseEMT activates exocytotic Rabs to coordinate invasion and immunosuppression in lung cancer.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 link2023-01-01T00:00:00Z2023 Jul2026-07-14T23:33:54.804Z2025-04-06T14:50:52.106ZS-EPMC103347513740609110.1073/pnas.2220276120