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Massachusetts General Hospital Cancer Center/Harvard Medical School (현 고려대학교)
Cancer Discov., March 28 2025, | https://doi.org/10.1158/2159-8290.CD-24-1317
LINE-1 ORF1p Mimics Viral Innate Immune Evasion Mechanisms in Pancreatic Ductal Adenocarcinoma
Eunae You 1, Bidish K. Patel 2, Alexandra S. Rojas 1, Siyu Sun 3, Patrick Danaher 4, Natalie I. Ho 1, Ildiko E. Phillips 1, Michael J. Raabe 2, Yuhui Song 1, Katherine H. Xu 2, Joshua R. Kocher 1, Peter M. Richieri 1, Phoebe Shin 1, Martin S. Taylor 5, Linda T. Nieman 1, Benjamin D. Greenbaum 6, David T. Ting 2
1Massachusetts General Hospital Cancer Center, Charlestown, MA, United States.
2Massachusetts General Hospital, Charlestown, MA, United States.
3Memorial Sloan Kettering Cancer Center, United States.
4Bruker Spatial Biology, Seattle, WA, United States.
5Brown University, Providence, RI, United States.
6Memorial Sloan Kettering Cancer Center, New York, United States.
*Corresponding Author: David T. Ting
1Massachusetts General Hospital Cancer Center, Charlestown, MA, United States.
2Massachusetts General Hospital, Charlestown, MA, United States.
3Memorial Sloan Kettering Cancer Center, United States.
4Bruker Spatial Biology, Seattle, WA, United States.
5Brown University, Providence, RI, United States.
6Memorial Sloan Kettering Cancer Center, New York, United States.
*Corresponding Author: David T. Ting
Abstract
Repeat element viral mimicry is a common feature in pancreatic ductal adenocarcinoma (PDAC) that require mechanisms to manage this repeat "viral" load and attenuate innate immune responses. Here, we show that the LINE-1 ORF1 protein (ORF1p) in PDAC cells plays a role in shielding repeat RNAs from activating a pathogen recognition receptor (PRR)-mediated antiviral response that is independent of retrotransposition. Suppression of ORF1p using short hairpin RNA induces innate immune responses through the dsRNA sensors RIG-I and MAVS. Low ORF1p PDAC cell lines have suppressed expression of PRRs demonstrating convergent mechanisms to suppress innate immune signaling. Localization of ORF1p in processing bodies (PBs) with the dsRNA helicase MOV10 were found important for these antiviral responses. Loss of ORF1p resulted in significant growth reduction in tumorspheres and mouse xenografts with an enriched epithelial cell state, and high ORF1p expression was associated with worsened survival in a cohort of human PDAC patients.
논문정보
- Research article
- 2025년 03월 (BRIC 등록일 2025-03-31)
- 국외 연구진
- 생명과학 > 세포생물학
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