Epstein-Barr virus infection upregulates extracellular OLFM4 to activate YAP signaling during gastric cancer progression

Fuping Wen, Yi Han, Hui Zhang, Zhangting Zhao, Wenjia Wang, Fan Chen, Weimin Qin, Junyi Ju, Liwei An, Yan Meng, Jie Yang, Yang Tang, Yun Zhao, Huanhu Zhang, Feng Li, Wenqi Bai (), Yuanzhi Xu (), Zhaocai Zhou () and Shi Jiao ()
Additional contact information
Fuping Wen: Tongji University School of Medicine
Yi Han: Tongji University School of Medicine
Hui Zhang: Fudan University
Zhangting Zhao: Tongji University School of Medicine
Wenjia Wang: Fudan University
Fan Chen: University of Chinese Academy of Sciences
Weimin Qin: Fudan University
Junyi Ju: Tongji University School of Medicine
Liwei An: Tongji University School of Medicine
Yan Meng: Tongji University School of Medicine
Jie Yang: Fudan University
Yang Tang: Tongji University School of Medicine
Yun Zhao: University of Chinese Academy of Sciences
Huanhu Zhang: Shanxi Cancer Hospital
Feng Li: Shanxi Cancer Hospital
Wenqi Bai: Shanxi Cancer Hospital
Yuanzhi Xu: Tongji University School of Medicine
Zhaocai Zhou: Fudan University
Shi Jiao: Fudan University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Extracellular vesicles (EVs) are known to mediate cell communications and shape tumor microenvironment. Compared to the well-studied small EVs, the function of large microvesicles (MVs) during tumorigenesis is poorly understood. Here we show the proteome of MVs in Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC), and identify olfactomedin 4 (OLFM4) is induced by EBV infection and secreted via MVs to promote tumor progression through Hippo signaling. Specifically, OLFM4 is a target gene of the cGAS-STING pathway, and EBV infection activates cGAS-STING pathway and increases OLFM4 expression. Moreover, MV-carried OLFM4 binds with the extracellular cadherin domain of FAT1, thereby impairing its intracellular interaction with MST1 and leading to YAP activation in recipient cells. Together, our study not only reveals a regulatory mechanism though which viral infection is coupled via MVs with intercellular control of the Hippo signaling, but also highlights the OLFM4-Hippo axis as a therapeutic target for EBV-associated cancers.

Date: 2024
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DOI: 10.1038/s41467-024-54850-6

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