EMT activates exocytotic Rabs to coordinate invasion and immunosuppression in lung cancer.
Guan-Yu XiaoXiaochao TanBertha L RodriguezDon L GibbonsShike WangChao WuXin LiuJiang YuMayra E VasquezHai T TranJun XuWilliam K RussellCara L HaymakerYounghee LeeJianjun ZhangLuisa SolisIgnacio I WistubaJonathan M KuriePublished in: Proceedings of the National Academy of Sciences of the United States of America (2023)
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.
Keyphrases
- epithelial mesenchymal transition
- signaling pathway
- cell migration
- transcription factor
- long non coding rna
- induced apoptosis
- cell proliferation
- quality improvement
- single cell
- stem cells
- biofilm formation
- staphylococcus aureus
- oxidative stress
- cell death
- pseudomonas aeruginosa
- pi k akt
- dna binding
- bone mineral density
- postmenopausal women