{"doi":"10.1172/jci165863","title":"EMT-activated secretory and endocytic vesicular trafficking programs underlie a vulnerability to PI4K2A antagonism in lung cancer","abstract":"Hypersecretory malignant cells underlie therapeutic resistance, metastasis, and poor clinical outcomes. However, the molecular basis for malignant hypersecretion remains obscure. Here, we showed that epithelial-mesenchymal transition (EMT) initiates exocytic and endocytic vesicular trafficking programs in lung cancer. The EMT-activating transcription factor zinc finger E-box-binding homeobox 1 (ZEB1) executed a PI4KIIIβ-to-PI4KIIα (PI4K2A) dependency switch that drove PI4P synthesis in the Golgi and endosomes. EMT enhanced the vulnerability of lung cancer cells to PI4K2A small-molecule antagonists. PI4K2A formed a MYOIIA-containing protein complex that facilitated secretory vesicle biogenesis in the Golgi, thereby establishing a hypersecretory state involving osteopontin (SPP1) and other prometastatic ligands. In the endosomal compartment, PI4K2A accelerated recycling of SPP1 receptors to complete an SPP1-dependent autocrine loop and interacted with HSP90 to prevent lysosomal degradation of AXL receptor tyrosine kinase, a driver of cell migration. These results show that EMT coordinates exocytic and endocytic vesicular trafficking to establish a therapeutically actionable hypersecretory state that drives lung cancer progression.","journal":"Journal of Clinical Investigation","year":2023,"id":334312,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":21,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9565,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":406591,"name":"Guan-Yu Xiao","orcid":"0000-0003-3454-6717","position":1,"is_corresponding":false},{"id":516608,"name":"Shike Wang","orcid":"0000-0003-3007-533X","position":2,"is_corresponding":false},{"id":228325,"name":"Lei Shi","orcid":"0000-0002-6043-8819","position":3,"is_corresponding":false},{"id":819826,"name":"Yanbin Zhao","orcid":"0000-0001-5632-5371","position":4,"is_corresponding":false},{"id":683523,"name":"Xin Liu","orcid":"0000-0001-5105-0532","position":5,"is_corresponding":false},{"id":311140,"name":"Yu Jiang","orcid":"0000-0001-5186-4587","position":6,"is_corresponding":false},{"id":250363,"name":"William K. Russell","orcid":"0000-0003-1931-4555","position":7,"is_corresponding":false},{"id":13376,"name":"Chad J. Creighton","orcid":"0000-0002-6090-703X","position":8,"is_corresponding":false},{"id":229781,"name":"Jonathan M. Kurie","orcid":null,"position":9,"is_corresponding":false},{"id":311135,"name":"Xiaochao Tan","orcid":"0000-0002-8603-5700","position":0,"is_corresponding":true}],"reference_count":70,"raw_metadata":null,"created_at":"2026-07-19T01:09:48.843291Z","pmid":"36757799","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}