Das Diganta, Iyer Mukund, Nakamura Brooke, Sedighi Saman, Hsu Angela, Danilov Camelia, LaViolette Peter S, Connelly Jennifer, Chow Frances, Neman Josh
Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
USC Brain Tumor Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Neuro Oncol. 2025 Jul 30;27(6):1476-1490. doi: 10.1093/neuonc/noaf027.
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.
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.
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.
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.
当肿瘤细胞与脉络丛上皮（CPE）相互作用，从而进入脑软膜和脑室系统中的脑脊液（CSF）时，就会发生软脑膜播散（LMD）。由于我们对此疾病了解有限且治疗选择较少，它对患者的危害极大。软脑膜脑脊液对肿瘤细胞来说是营养匮乏的微环境。尽管如此，LMD肿瘤细胞通过摄取和代谢脑脊液中的神经递质γ-氨基丁酸（GABA）得以存活。然而，我们目前缺乏关于脑脊液中GABA水平如何改变以及肿瘤细胞如何与CPE沟通以提高LMD微环境中GABA水平的证据。在此，我们研究了CPE与肿瘤细胞之间的相互作用，正是这些相互作用使得脑脊液对LMD生长更具适宜性。
将原代脉络丛、乳腺癌细胞以及患者来源的乳腺和肺脑转移细胞用于体内转移/LMD建模，并使用信号转导和转录激活因子6（STAT6）抑制剂以及IL13基因敲低技术。
我们发现源自乳腺癌和肺癌细胞的IL13激活了脉络丛中的STAT6信号通路。随后，脉络丛上调GABA合成酶GAD67和GABA可渗透通道Bestrophin1，所有这些都导致脑脊液中神经递质GABA水平升高。此外，我们发现当肿瘤来源的IL13被敲低或用可透过血脑屏障的STAT6特异性抑制剂AS1517499处理时，脉络丛中Bestrophin1显著减少，从而导致存活率提高。
总体而言，这些发现揭示了脉络丛中一条新的STAT6 - Bestrophin1 - GABA轴，对其进行治疗靶向可能会在软脑膜疾病中带来良好的治疗效果。
