ArticleJournal of advanced research2026
KRAS/ACTN4/p65-NR2A axis mediates glutamine-glutamate metabolic coupling between schwann cells and pancreatic cancer promoting perineural invasion.
Article in Journal of advanced research, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- Lysosomal lipid metabolism promotes tumor cell invasion through local energetics and membrane lipid remodeling.bioRxiv : the preprint server for biology · 2026Article
- Metabolic reprogramming in cancer: dysregulation of glucose, lipid, and amino acid pathways and therapeutic opportunities.Molecular biomedicine · 2026Review
- PIEZO1 enhances pancreatic cancer neurotropism.Cancer cell international · 2026Article
- Enteric neuro-immune-tumor ecosystem in pancreatic, colorectal, and gastric malignancies: context dependence and translational priorities.Frontiers in immunology · 2026Review
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Authors and funding
6 authors.
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Abstract
introductionPancreatic ductal adenocarcinoma (PDAC) exhibits aggressive perineural invasion (PNI), a hallmark of poor prognosis observed in 70-100% of cases. Schwann cells (SCs), key components of the tumor microenvironment, drive PNI via multiple pathways, yet the underlying mechanisms remain unclear.
objectivesThis study investigates the hypothesis that PDAC cells and SCs establish a glutamine-glutamate metabolic symbiosis to fuel PNI.
methodsIntegrated approaches, including LC-MS metabolomics, isotopic tracing, co-culture systems, and in vivo models, were employed to analyze bidirectional metabolite exchange. Molecular assays and functional studies elucidated signaling pathways. The therapeutic potential of targeting glutamine transporters (SLC1A5/SLC7A5) and glutamate receptor NR2A was tested using inhibitors V9302 and PEAQX.
resultsSCs secreted glutamine, which PDAC cells internalized via SLC1A5 and converted to glutamate. Glutamate activated SCs through NR2A, inducing ROS/NRF2-expression and upregulating glutamine synthetase (GS) and GLT-1, thereby regenerating glutamine to sustain the metabolic loop. KRAS-ACTN4-p65 signaling amplified this cycle by transcriptionally activating SLC1A5/SLC7A5 and GLS, while leucine uptake via SLC7A5 activated mTORC1 to promote invasion and PNI. In vivo, dual inhibition of SLC1A5/SLC7A5 (V9302) and NR2A (PEAQX) synergistically reduced tumor growth, PNI length, and improved sciatic nerve function in mice.
conclusionThis study identifies a reciprocal glutamine-glutamate metabolic symbiosis between PDAC cells and SCs as a driver of PNI, orchestrated by KRAS-ACTN4-NF-κB signaling and glutamate-NR2A-ROS-NRF2 pathways. Disrupting this axis with V9302 and PEAQX offers a novel therapeutic strategy to target PDAC's metabolic adaptability and neurotrophic microenvironment.
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