Epstein-Barr virus infection upregulates extracellular OLFM4 to activate YAP signaling during gastric cancer progression
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.
Authors
- Wenqi Bai (ORCID: https://orcid.org/0000-0002-7142-6805)
- Wen Qin (ORCID: https://orcid.org/0000-0002-2714-3613)
- Junyi Ju
- Fuping Wen (ORCID: https://orcid.org/0009-0005-3153-9820)
- Yang Tang (ORCID: https://orcid.org/0000-0002-2750-8029)
- Hui Zhang (ORCID: https://orcid.org/0000-0002-7358-5375)
- Zhaocai Zhou (ORCID: https://orcid.org/0000-0002-5441-3922)
- Zhangting Zhao (ORCID: https://orcid.org/0000-0002-4481-946X)
- Huanhu Zhang (ORCID: https://orcid.org/0000-0003-1641-2520)
- Yi Han (ORCID: https://orcid.org/0009-0004-0687-4945)
- Feng Li (ORCID: https://orcid.org/0000-0002-7419-232X)
- Wenjia Wang (ORCID: https://orcid.org/0000-0002-2892-6214)
- Liwei An (ORCID: https://orcid.org/0000-0003-4514-5476)
- Shi Jiao (ORCID: https://orcid.org/0000-0003-3591-8973)
- Y-Y Xu (ORCID: https://orcid.org/0009-0000-0572-7100)
- Fan Chen (ORCID: https://orcid.org/0000-0003-4905-1880)
- Jie Yang (ORCID: https://orcid.org/0000-0003-1439-6504)
- Yun Zhao (ORCID: https://orcid.org/0000-0002-7807-6094)
- Meng Yan
Institutions
- Tongji University (CN)
- Fudan University (CN)
- Shanxi Provincial Cancer Hospital (CN)
- Shanghai Institutes for Biological Sciences (CN)
- Ministry of Education (KR)
- Center for Excellence in Molecular Cell Science (CN)
- Zhongshan Hospital (CN)
- Shanghai Tenth People's Hospital (CN)
- University of Chinese Academy of Sciences (CN)
- Nanjing Medical University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-12-03
- DOI
- https://doi.org/10.1038/s41467-024-54850-6
- Citations
- 12
- Primary Topic
- Extracellular vesicles in disease
- Type
- article
- Field-Weighted Citation Impact
- 2.81
Funders
- National Natural Science Foundation of China
- Sun Yat-sen University
- China Postdoctoral Science Foundation
- Science and Technology Commission of Shanghai Municipality