{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T01:16:06Z","timestamp":1792286166817,"version":"4.4.0"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2025,1,30]],"date-time":"2025-01-30T00:00:00Z","timestamp":1738195200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01CA223544-01A1"],"award-info":[{"award-number":["R01CA223544-01A1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1R01NS133038"],"award-info":[{"award-number":["1R01NS133038"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01CA218144"],"award-info":[{"award-number":["R01CA218144"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01CA249882"],"award-info":[{"award-number":["R01CA249882"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["S10OD021785"],"award-info":[{"award-number":["S10OD021785"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["S10OD018096"],"award-info":[{"award-number":["S10OD018096"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30CA014089"],"award-info":[{"award-number":["P30CA014089"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","award":["KL2TR001854"],"award-info":[{"award-number":["KL2TR001854"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000048","name":"American Cancer Society","doi-asserted-by":"publisher","award":["IRG-22-144-60"],"award-info":[{"award-number":["IRG-22-144-60"]}],"id":[{"id":"10.13039\/100000048","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,7,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Leptomeningeal dissemination (LMD) occurs when tumor cells interact with choroid plexus epithelium (CPE) to gain access to cerebrospinal fluid (CSF) in the brain\u2019s 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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/neuonc\/noaf027","type":"journal-article","created":{"date-parts":[[2025,1,30]],"date-time":"2025-01-30T10:31:21Z","timestamp":1738233081000},"page":"1476-1490","source":"Crossref","is-referenced-by-count":9,"title":["Tumor cells upregulate neurotransmitter GABA in the choroid plexus through STAT6-Bestrophin1 signaling, promoting leptomeningeal dissemination"],"prefix":"10.1093","volume":"27","author":[{"given":"Diganta","family":"Das","sequence":"first","affiliation":[{"name":"Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California , Los Angeles, California,","place":["USA"]},{"name":"USC Brain Tumor Center, Keck School of Medicine, University of Southern California , Los Angeles, California,","place":["USA"]},{"name":"Department of Neurological Surgery, Keck School of Medicine, University of Southern California , Los Angeles, California,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mukund","family":"Iyer","sequence":"additional","affiliation":[{"name":"Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California , Los Angeles, California,","place":["USA"]},{"name":"USC Brain Tumor Center, Keck School of Medicine, University of Southern California , Los Angeles, California,","place":["USA"]},{"name":"Department of Neurological Surgery, Keck School of Medicine, University of Southern California , Los Angeles, California,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brooke","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California , Los Angeles, California,","place":["USA"]},{"name":"USC Brain Tumor Center, Keck School of Medicine, University of Southern California , Los Angeles, California,","place":["USA"]},{"name":"Department of Neurological Surgery, Keck School of Medicine, University of Southern California , Los Angeles, California,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saman","family":"Sedighi","sequence":"additional","affiliation":[{"name":"Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California , Los Angeles, California,","place":["USA"]},{"name":"USC Brain Tumor Center, Keck School of Medicine, University of Southern California , Los Angeles, California,","place":["USA"]},{"name":"Department of Neurological Surgery, Keck School of Medicine, University of Southern California , Los Angeles, California,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Hsu","sequence":"additional","affiliation":[{"name":"Life Science Department, University of Bristol , Bristol,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camelia","family":"Danilov","sequence":"additional","affiliation":[{"name":"Department of Neurological Surgery, Keck School of Medicine, University of Southern California , Los Angeles, California,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter S","family":"LaViolette","sequence":"additional","affiliation":[{"name":"Department of Radiology, Biophysics, and Biomedical Engineering, Medical College of Wisconsin , Milwaukee, Wisconsin,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Connelly","sequence":"additional","affiliation":[{"name":"Department of Neurology, Medical College of Wisconsin , Milwaukee, Wisconsin,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frances","family":"Chow","sequence":"additional","affiliation":[{"name":"Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California , Los Angeles, California,","place":["USA"]},{"name":"USC Brain Tumor Center, Keck School of Medicine, University of Southern California , Los Angeles, California,","place":["USA"]},{"name":"Department of Neurological Surgery, Keck School of Medicine, University of Southern California , Los Angeles, 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