Tumor cells upregulate neurotransmitter GABA in the choroid plexus through STAT6-Bestrophin1 signaling, promoting leptomeningeal dissemination.

Abstract

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 GABA from the CSF. However, we currently lack evidence on how CSF-GABA levels are altered and how tumor cells communicate with the choroid plexus epithelium 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: We utilized primary choroid plexus, breast cancer cell and patient-derived breast and lung to brain metastatic cells along with in-vivo modeling along with 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 Bestrophin-1, all leading to elevated neurotransmitter GABA levels in the cerebrospinal fluid. 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.