ArticleNeuro-oncology2025
Tumor cells upregulate neurotransmitter GABA in the choroid plexus through STAT6-Bestrophin1 signaling, promoting leptomeningeal dissemination.
Article in Neuro-oncology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- Lung Cancer Brain Metastasis: Brain Microenvironmental Adaptation, Therapeutic Resistance and Translational Strategies.Cancer science · 2026Review
- Targeting the nervous system: Mechanistic insights into neuro-tumor communication and therapeutic opportunities.Acta pharmaceutica Sinica. B · 2026Review
- Neural regulation in lung cancer: from mechanisms to new therapeutic perspectives.Clinical and experimental medicine · 2026Review
- The immune microenvironment of the central nervous system and neuromodulation: new perspectives in lung cancer brain metastases research.Frontiers in immunology · 2026Review
- Therapeutic radiation drives leptomeningeal dissemination of medulloblastoma through an innate immune process.Developmental cell · 2025Article
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Authors and funding
10 authors.
Funding
Abstract
backgroundLeptomeningeal dissemination (LMD) occurs when tumor cells interact with choroid plexus epithelium (CPE) to gain access to cerebrospinal fluid (CSF) in the brain's meninges and ventricular system. This disease is particularly devastating for patients due to our limited understanding and few therapeutic options. The leptomeningeal CSF is a nutritionally deprived microenvironment for tumor cells. Despite this, LMD tumor cells survive by taking up and metabolizing the neurotransmitter gamma-aminobutyric acid (GABA) from the CSF. However, we currently lack evidence on how CSF-GABA levels are altered and how tumor cells communicate with the CPE to increase GABA levels in the LMD microenvironment. Herein, we examined the interactions between CPEs and tumor cells that make CSF more hospitable to LMD growth.
methodsPrimary choroid plexus, breast cancer cells, and patient-derived breast and lung-to-brain metastatic cells, are utilized in in vivo metastatic /LMD modeling along with signal transducer and activator of transcription 6 (STAT6) inhibitor and IL13 gene knockdown.
resultsWe show breast and lung cancer cells derived-IL13 activates STAT6 signaling in choroid plexus. Subsequently, choroid plexus upregulates GABA-synthesizing enzyme GAD67 and GABA-permeable channel Bestrophin1, all leading to elevated neurotransmitter GABA levels in the CSF. Moreover, we show a significant reduction of Bestrophin1 in choroid plexus when tumor-derived IL13 is knocked down or when treated with brain permeable STAT6 specific inhibitor AS1517499, leading to increased survival.
conclusionsOverall, these findings reveal a novel STAT6-Bestrophin1-GABA axis in choroid plexus and its therapeutic targeting can lead to favorable outcomes in leptomeningeal disease.
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