EMT-activated secretory and endocytic vesicular trafficking programs underlie a vulnerability to PI4K2A antagonism in lung cancer

作者：Tan, Xiaochao^*; Xiao, Guan-Yu; Wang, Shike; Shi, Lei; Zhao, Yanbin; Liu, Xin; Yu, Jiang; Russell, William K.; Creighton, Chad J.; Kurie, Jonathan M.^*

来源：Journal of Clinical Investigation, 2023, 133(7): e165863.

DOI：10.1172/JCI165863

• EPITHELIAL-MESENCHYMAL TRANSITION
• PHOSPHATIDYLINOSITOL 4-KINASES
• MIR-200 FAMILY
• FEEDBACK LOOP
• GOLGI
• ZEB1
• METASTASIS
• PROMOTE
• PROTEIN
• PI4KII-ALPHA

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 PI4KIII beta-to-PI4KII alpha (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.

• 单位
  432; 哈尔滨医科大学