EMT-Activated Secretory and Endocytic Vesicular Trafficking Programs Underlie a Vulnerability to PI4K2A Antagonism in Lung Cancer

Authors

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

Language

English

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

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.

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

Published Open-Access

yes

Recommended Citation

Tan, Xiaochao; Xiao, Guan-Yu; Wang, Shike; et al., "EMT-Activated Secretory and Endocytic Vesicular Trafficking Programs Underlie a Vulnerability to PI4K2A Antagonism in Lung Cancer" (2023). Faculty and Staff Publications. 1556.
https://digitalcommons.library.tmc.edu/baylor_docs/1556