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

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

Research output: Contribution to journalArticlepeer-review


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 smallmolecule 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.

Original languageEnglish
Article numbere165863
JournalJournal of Clinical Investigation
Issue number7
StatePublished - Apr 3 2023

Bibliographical note

Funding Information:
This work was supported in part by the NIH (R01CA236781 and R01CA255021-01, to JMK) and The Lung Cancer Research Foundation (to XT). The UTMB Mass Spectrometry Facility is supported in part by Cancer Prevention & Research Institute of Texas (CPRIT) grant RP190682 (to WKR). JMK holds the Gloria Lupton Tennison Distinguished Professorship in Lung Cancer. We thank Priyam Banerjee (The Rockefeller University, New York, New York, USA) for constructive criticism of the manuscript.

Publisher Copyright:
© 2023, Tan et al.

ASJC Scopus subject areas

  • Medicine (all)


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