Tumor cells upregulate neurotransmitter GABA in the choroid plexus through STAT6-Bestrophin1 signaling, promoting leptomeningeal dissemination. Neuro Oncol 2025 Jul 30;27(6):1476-1490
Date
01/30/2025Pubmed ID
39883056Pubmed Central ID
PMC12309716DOI
10.1093/neuonc/noaf027Scopus ID
2-s2.0-105012240300 (requires institutional sign-in at Scopus site) 1 CitationAbstract
BACKGROUND: Leptomeningeal 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.
METHODS: Primary 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.
RESULTS: We 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.
CONCLUSIONS: Overall, these findings reveal a novel STAT6-Bestrophin1-GABA axis in choroid plexus and its therapeutic targeting can lead to favorable outcomes in leptomeningeal disease.
Author List
Das D, Iyer M, Nakamura B, Sedighi S, Hsu A, Danilov C, LaViolette PS, Connelly J, Chow F, Neman JAuthors
Jennifer M. Connelly MD Professor in the Neurology department at Medical College of WisconsinPeter LaViolette PhD Vice Chair, Professor in the Radiology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsBestrophins
Choroid Plexus
Female
Humans
Meningeal Neoplasms
Mice
STAT6 Transcription Factor
Signal Transduction
Tumor Cells, Cultured
Up-Regulation
gamma-Aminobutyric Acid
