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

Authors

Xiaochao Tan, The University of Texas MD Anderson Cancer CenterFollow
Guan-Yu Xiao, The University of Texas MD Anderson Cancer Center
Shike Wang, The University of Texas MD Anderson Cancer Center
Lei Shi, The University of Texas MD Anderson Cancer Center
Yanbin Zhao, The University of Texas MD Anderson Cancer Center; Harbin Medical University Cancer Hospital
Xin Liu, The University of Texas MD Anderson Cancer Center
Jiang Yu, The University of Texas MD Anderson Cancer Center
William K. Russell, The University of Texas Medical Branch
Chad J. Creighton, Baylor College of Medicine; The University of Texas MD Anderson Cancer Center
Jonathan M. Kurie, The University of Texas MD Anderson Cancer CenterFollow

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.

Document Type

Article

Publication Date

4-2023

Notes/Citation Information

© 2023, Tan et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License

Digital Object Identifier (DOI)

https://doi.org/10.1172/JCI165863

Funding Information

This work was supported in part by the NIH (R01CA236781 and R01CA255021-01, to JMK) and The Lung Cancer Research Foun- dation (to XT). The UTMB Mass Spectrometry Facility is support- ed 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.

Repository Citation

Tan, Xiaochao; Xiao, Guan-Yu; Wang, Shike; Shi, Lei; Zhao, Yanbin; Liu, Xin; Yu, Jiang; Russell, William K.; Creighton, Chad J.; and Kurie, Jonathan M., "EMT-activated secretory and endocytic vesicular trafficking programs underlie a vulnerability to PI4K2A antagonism in lung cancer" (2023). Markey Cancer Center Faculty Publications. 328.
https://uknowledge.uky.edu/markey_facpub/328