ArticleJournal of virology2025
METTL3 depletion blocks vesicular stomatitis virus replication in pancreatic cancer cells through the establishment of an intrinsic antiviral state.
Article in Journal of virology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- The OAS1-FASN axis promotes pancreatic cancer by coordinating lipogenic stress and the unfolded protein response.Cell death & disease · 2026Article
- Engineering strategies to address immune and delivery barriers in pancreatic ductal adenocarcinoma: a barrier-matched translational framework.Frontiers in immunology · 2026Review
- Fostamatinib (R788), a spleen tyrosine kinase inhibitor, sensitizes pancreatic cancer cells to oncolytic vesicular stomatitis virus.Molecular therapy. Oncology · 2025Article
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Authors and funding
5 authors.
Funding
Abstract
Vesicular stomatitis virus (VSV) is a promising oncolytic virus (OV) against different malignancies, including pancreatic ductal adenocarcinoma (PDAC). In this study, we examined the role of methyltransferase-like 3 (METTL3), a catalytic subunit of the cellular writer complex that is responsible for N6-methyladenosine (m6A) RNA modification, as a potential host factor of VSV replication in PDAC cells. METTL3 was previously shown to be upregulated in PDAC, where it promotes cancer cell proliferation, invasion, and chemoresistance. The impact of METTL3 on life cycles of different viruses varies depending on both the virus and the cell type. Additionally, METTL3 plays a positive role in VSV replication in non-PDAC cells via m6A modification of VSV RNAs, which attenuates innate antiviral responses. In this study, we examined the role of METTL3 in 10 different human PDAC cell lines and uncovered two distinct outcomes. METTL3 depletion did not affect VSV replication in PDAC cell lines with defective innate antiviral signaling, suggesting that METTL3 is not directly involved in VSV replication. In contrast, METTL3 depletion dramatically inhibited VSV replication in PDAC cell lines with functional antiviral signaling. We show that this result is due to the RIG-I-dependent induction of a virus-independent, intrinsic antiviral state in METTL3-depleted PDAC cells. This intrinsic antiviral state was marked by type-III (but not type I or II) interferon secretion and constitutive overexpression of antiviral sensors [RIG-I (DDX58), MDA5 (IFIH1), and LGP2 (DHX58)], transactivators (STAT1, IRF7, and IRF9), and a diverse subset of antiviral effectors, including MX1, OAS1/2/3, and IFIT1/3.IMPORTANCEPancreatic cancer is a deadly and extremely challenging disease, making it essential to develop new treatment options and improve patient survival rates. One promising approach is the use of replication-competent "oncolytic viruses" designed to specifically target and destroy cancer cells while sparing healthy ones. To create effective oncolytic virus therapies for pancreatic cancer, it is crucial to identify host factors that influence the successful infection of cancer cells by these viruses. Here, we demonstrate that the cellular protein METTL3, which was previously shown to promote pancreatic cancer cell proliferation, invasion, and resistance to chemotherapy, plays a positive role in oncolytic virus replication in most of the tested human pancreatic cancer cell lines. We demonstrate that METTL3 depletion induces a chronic antiviral state that dramatically inhibits viral replication. Our study is important for understanding and improving oncolytic virus-based therapies.
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