Publication Date
4-3-2023
Journal
Journal of Clinical Investigation
DOI
10.1172/JCI165863
PMID
36757799
PMCID
PMC10065074
PubMedCentral® Posted Date
4-3-2023
PubMedCentral® Full Text Version
Post-Print
Published Open-Access
yes
Keywords
Humans, Epithelial-Mesenchymal Transition, Cell Line, Tumor, Lung Neoplasms, Zinc Finger E-box-Binding Homeobox 1, Secretory Vesicles, Gene Expression Regulation, Neoplastic, Cell Biology, Oncology, Cancer gene therapy, Lung cancer, Oncogenes
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.
Graphical Abstract
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Genetic Phenomena Commons, Internal Medicine Commons, Medical Genetics Commons, Oncology Commons, Pulmonology Commons
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