ArticleCancer letters2025
Glycosaminoglycan modification of NRP1 exon 4-skipping variant drives colorectal cancer metastasis via endosomal-exosomal trafficking.
Article in Cancer letters, 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 'sugar' side of extracellular vesicle-glycome: a panorama from basic characteristics, deciphering technologies, functions, to applications.Journal of nanobiotechnology · 2026Review
- Hexavalent chromium promotes malignant transformation via enhanced translation of SUV39H1.Chemico-biological interactions · 2026Article
- Targeting Neuropilin-1 for Cancer Pain Treatment: A Trial With Potential for Clinical Translation.Cancer control : journal of the Moffitt Cancer CenterReview
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Authors and funding
6 authors.
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Abstract
Neuropilin-1 (NRP1) is a transmembrane glycoprotein that functions as a co-receptor with various cellular functions. Our previous studies identified the NRP1 exon 4-skipping (NRP1-ΔE4) splice variant as an aggressive metastasis driver by activating endosomal signals. Here, we demonstrate the critical role of glycosaminoglycan (GAG) modification in regulating NRP1-ΔE4's cellular trafficking and oncogenic activity. NRP1-ΔE4 undergoes constitutive internalization into endosomes and subsequent exosomal release from colorectal cancer (CRC) cells. Exosomal NRP1-ΔE4 enhances the migration and invasion of both donor and recipient CRC cells. Genetic or pharmacological inhibition of exosome secretion, or immunodepletion of exosomal NRP1-ΔE4, markedly reduces its metastatic potential. Notably, GAG modification at the O-glycosylation site Ser612 is essential for NRP1-ΔE4's endosomal trafficking and exosomal release. This modification also promotes the formation of a trimeric complex with Met and β1-integrin, leading to their co-internalization and accumulation in endosomes, which activates FAK signaling and drives CRC metastasis. These findings reveal GAG modification as a key regulatory process that governs the endosomal-exosomal trafficking of NRP1-ΔE4 to facilitate CRC cell dissemination.
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