2. Academic Validation
  3. Epstein-Barr virus infection upregulates extracellular OLFM4 to activate YAP signaling during gastric cancer progression

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

  • Nat Commun. 2024 Dec 4;15(1):10543. doi: 10.1038/s41467-024-54850-6.
Fuping Wen # 1,  Yi Han # 1,  Hui Zhang # 2,  Zhangting Zhao # 1,  Wenjia Wang # 2,  Fan Chen 3,  Weimin Qin 2,  Junyi Ju 1,  Liwei An 1,  Yan Meng 1,  Jie Yang 2,  Yang Tang 1,  Yun Zhao 3,  Huanhu Zhang 4,  Feng Li 4,  Wenqi Bai 5,  Yuanzhi Xu 6,  Zhaocai Zhou 7 8,  Shi Jiao 9
Affiliations

Affiliations

  • 1 Department of Stomatology, Shanghai Tenth People's Hospital, Tongji University Cancer Center, Tongji University School of Medicine, Shanghai, 200072, China.
  • 2 State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200438, China.
  • 3 CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China.
  • 4 Department of Digestive Sciences, Shanxi Cancer Hospital, Taiyuan, 030001, China.
  • 5 Department of Digestive Sciences, Shanxi Cancer Hospital, Taiyuan, 030001, China. wenqibai2022@163.com.
  • 6 Department of Stomatology, Shanghai Tenth People's Hospital, Tongji University Cancer Center, Tongji University School of Medicine, Shanghai, 200072, China. xuyuanzhi@tongji.edu.cn.
  • 7 State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200438, China. zhouzhaocai@fudan.edu.cn.
  • 8 Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, 211166, China. zhouzhaocai@fudan.edu.cn.
  • 9 State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200438, China. jiaoshi@fudan.edu.cn.
  • # Contributed equally.
PMID: 39627192 DOI: 10.1038/s41467-024-54850-6
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.

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