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

doi:10.1172/JCI165863

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 journal › Article › peer-review

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 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 language	English
Article number	e165863
Journal	Journal of Clinical Investigation
Volume	133
Issue number	7
DOIs	https://doi.org/10.1172/JCI165863
State	Published - 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)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1172/JCI165863

Cite this

@article{ba13144e8f21422ca3ed9b1bf43aa440,

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

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 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.",

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

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: {\textcopyright} 2023, Tan et al.",

year = "2023",

month = apr,

day = "3",

doi = "10.1172/JCI165863",

language = "English",

volume = "133",

number = "7",

}

TY - JOUR

T1 - EMT-activated secretory and endocytic vesicular trafficking programs underlie a vulnerability to PI4K2A antagonism in lung cancer

AU - Tan, Xiaochao

AU - Xiao, Guan Yu

AU - Wang, Shike

AU - Shi, Lei

AU - Zhao, Yanbin

AU - Liu, Xin

AU - Yu, Jiang

AU - Russell, William K.

AU - Creighton, Chad J.

AU - Kurie, Jonathan M.

N1 - 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.

PY - 2023/4/3

Y1 - 2023/4/3

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85151575536&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85151575536&partnerID=8YFLogxK

U2 - 10.1172/JCI165863

DO - 10.1172/JCI165863

M3 - Article

C2 - 36757799

AN - SCOPUS:85151575536

SN - 0021-9738

VL - 133

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 7

M1 - e165863

ER -

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

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this