ArticleCancer research2026
Extracellular Vesicle-Mediated O-GlcNAcase Transfer Drives Neuronal Necroptosis to Facilitate Gallbladder Cancer Perineural Invasion.
Article in Cancer research, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
What it found
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Who cites it
5 citing papers in PubMed.
- Neural regulation of cancer: from microenvironmental hijacking to systemic circuit co-option.Cellular oncology (Dordrecht, Netherlands) · 2026Review
- Circadian rhythms in the tumor microenvironment: spatiotemporal immune regulation and chronotherapeutic opportunities.Frontiers in immunology · 2026Review
- Prognostic Stratification and Subtyping of Glioblastoma Using Transient Receptor Potential Channels.Human mutation · 2026Article
- Neural-immune-cancer crosstalk in pancreatic cancer: mechanisms and clinical translation.Frontiers in cell and developmental biology · 2026Review
- Perineural invasion in solid tumors: biological foundations and the emerging integration of machine learning and artificial intelligence.Frontiers in oncology · 2026Review
Corrections and comments
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Authors and funding
19 authors.
Funding
Abstract
Peripheral nerve invasion (PNI) is an early and decisive step in gallbladder cancer progression that strongly predicts poor postsurgical outcome. The tumor-neuron interactions that drive PNI could represent potential targets and biomarkers to improve treatment of gallbladder cancer. In this study, we demonstrated that gallbladder cancer provoked necroptosis of neurons to enable PNI. Gallbladder cancer cells transferred extracellular vesicles (EV) containing O-GlcNAcase (OGA) to neurons, which activated RIPK1-dependent necroptosis. Mechanistically, EV-derived OGA suppressed RIPK1 glycosylation while enhancing its phosphorylation, thereby activating the RIPK1/RIPK3/MLKL axis to trigger neuronal necroptosis. Subsequent neuronal release of HMGB1 engaged RAGE on gallbladder cancer cells, establishing a loop that accelerated PNI. Moreover, the RAGE antagonist FPS-ZM1 synergized with gemcitabine to suppress tumor progression. Collectively, these findings uncover an EV-mediated cross-talk between gallbladder cancer cells and neurons in which RIPK1-dependent necroptosis and its effector HMGB1 drive PNI, positioning the HMGB1-RAGE axis as a tractable therapeutic target. SIGNIFICANCE: Tumor-derived extracellular vesicles trigger neuronal necroptosis that fuels peripheral nerve invasion, creating a tumor-neuron signaling loop that could be leveraged for liquid biopsy and personalized therapy strategies in neurotropic cancers.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.