{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T06:00:16Z","timestamp":1792648816323,"version":"4.5.0"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2022,2,25]],"date-time":"2022-02-25T00:00:00Z","timestamp":1645747200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P50 CA168536"],"award-info":[{"award-number":["P50 CA168536"]}],"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":["R21 CA198550"],"award-info":[{"award-number":["R21 CA198550"]}],"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":["R21 CA216756"],"award-info":[{"award-number":["R21 CA216756"]}],"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":["K99 CA226679"],"award-info":[{"award-number":["K99 CA226679"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","award":["W81XWH1810268"],"award-info":[{"award-number":["W81XWH1810268"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["P30-CA076292"],"award-info":[{"award-number":["P30-CA076292"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,10,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Leptomeningeal disease (LMD) occurs as a late complication of several human cancers and has no rationally designed treatment options. A major barrier to developing effective therapies for LMD is the lack of cell-based or preclinical models that recapitulate human disease. Here, we describe the development of in vitro and in vivo cultures of patient-derived cerebrospinal fluid circulating tumor cells (PD-CSF-CTCs) from patients with melanoma as a preclinical model to identify exploitable vulnerabilities in melanoma LMD.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>CSF-CTCs were collected from melanoma patients with melanoma-derived LMD and cultured ex vivo using human meningeal cell-conditioned media. Using immunoassays and RNA-sequencing analyses of PD-CSF-CTCs, molecular signaling pathways were examined and new therapeutic targets were tested for efficacy in PD-CSF-CTCs preclinical models.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>PD-CSF-CTCs were successfully established both in vitro and in vivo. Global RNA analyses of PD-CSF-CTCs revealed several therapeutically tractable targets. These studies complimented our prior proteomic studies highlighting IGF1 signaling as a potential target in LMD. As a proof of concept, combining treatment of ceritinib and trametinib in vitro and in vivo demonstrated synergistic antitumor activity in PD-CSF-CTCs and BRAF inhibitor-resistant melanoma cells.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>This study demonstrates that CSF-CTCs can be grown in vitro and in vivo from some melanoma patients with LMD and used as preclinical models. These models retained melanoma expression patterns and had signaling pathways that are therapeutically targetable. These novel models\/reagents may be useful in developing rationally designed treatments for LMD.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/neuonc\/noac054","type":"journal-article","created":{"date-parts":[[2022,2,24]],"date-time":"2022-02-24T12:11:05Z","timestamp":1645704665000},"page":"1673-1686","source":"Crossref","is-referenced-by-count":17,"title":["A preclinical model of patient-derived cerebrospinal fluid circulating tumor cells for experimental therapeutics in leptomeningeal disease from melanoma"],"prefix":"10.1093","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8569-1378","authenticated-orcid":false,"given":"Vincent","family":"Law","sequence":"first","affiliation":[{"name":"Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute , Tampa, Florida , USA"},{"name":"Department of Neuro-Oncology, H. Lee Moffitt Cancer Center & Research Institute , Tampa, Florida , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihua","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute , Tampa, Florida , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Vena","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery, H. Lee Moffitt Cancer Center & Research Institute , Tampa, Florida , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inna","family":"Smalley","sequence":"additional","affiliation":[{"name":"Department of Cancer Physiology, H. Lee Moffitt Cancer Center & Research Institute , Tampa, Florida , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Macaulay","sequence":"additional","affiliation":[{"name":"Department of Pathology, H. Lee Moffitt Cancer Center & Research Institute , Tampa, Florida , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brittany R","family":"Evernden","sequence":"additional","affiliation":[{"name":"Department of Analytic Microscopy, H. Lee Moffitt Cancer Center & Research Institute , Tampa, Florida , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nam","family":"Tran","sequence":"additional","affiliation":[{"name":"Department of Analytic Microscopy, H. Lee Moffitt Cancer Center & Research Institute , Tampa, Florida , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yolanda","family":"Pina","sequence":"additional","affiliation":[{"name":"Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute , Tampa, Florida , USA"},{"name":"Department of Analytic Microscopy, H. Lee Moffitt Cancer Center & Research Institute , Tampa, Florida , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Puskas","sequence":"additional","affiliation":[{"name":"Department of Pathology, H. Lee Moffitt Cancer Center & Research Institute , Tampa, Florida , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gisela","family":"Caceres","sequence":"additional","affiliation":[{"name":"Department of Pathology, H. Lee Moffitt Cancer Center & Research Institute , Tampa, Florida , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Bayle","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery, H. Lee Moffitt Cancer Center & Research Institute , Tampa, Florida , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Analytic Microscopy, H. Lee Moffitt Cancer Center & Research Institute , Tampa, Florida , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James K C","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neuro-Oncology, H. Lee Moffitt Cancer Center & Research Institute , Tampa, Florida , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnold","family":"Etame","sequence":"additional","affiliation":[{"name":"Department of Neuro-Oncology, H. Lee Moffitt Cancer Center & Research Institute , Tampa, Florida , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Vogelbaum","sequence":"additional","affiliation":[{"name":"Department of Neuro-Oncology, H. Lee Moffitt Cancer Center & Research Institute , Tampa, Florida , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paulo","family":"Rodriguez","sequence":"additional","affiliation":[{"name":"Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute , Tampa, Florida , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derek","family":"Duckett","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery, H. Lee Moffitt Cancer Center & Research Institute , Tampa, Florida , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Czerniecki","sequence":"additional","affiliation":[{"name":"Department of Breast Oncology, H. Lee Moffitt Cancer Center & Research Institute , Tampa, Florida , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute , Tampa, Florida , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiran S M","family":"Smalley","sequence":"additional","affiliation":[{"name":"Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute , Tampa, Florida , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter A","family":"Forsyth","sequence":"additional","affiliation":[{"name":"Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute , Tampa, Florida , USA"},{"name":"Department of Neuro-Oncology, H. Lee Moffitt Cancer Center & Research Institute , Tampa, Florida , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,2,25]]},"reference":[{"issue":"4","key":"2022100306594699400_CIT0001","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1111\/pcmr.12861","article-title":"Leptomeningeal disease in melanoma patients: an update to treatment, challenges, and future directions","volume":"33","author":"Glitza","year":"2020","journal-title":"Pigment Cell Melanoma Res"},{"issue":"9","key":"2022100306594699400_CIT0002","doi-asserted-by":"crossref","first-page":"2163","DOI":"10.1158\/1078-0432.CCR-19-2840","article-title":"Proteomic analysis of CSF from patients with leptomeningeal melanoma metastases identifies signatures associated with disease progression and therapeutic resistance","volume":"26","author":"Smalley","year":"2020","journal-title":"Clin Cancer Res."},{"issue":"16","key":"2022100306594699400_CIT0003","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.1056\/NEJMoa1910836","article-title":"Five-year survival with combined nivolumab and ipilimumab in advanced melanoma","volume":"381","author":"Larkin","year":"2019","journal-title":"N Engl J Med."},{"issue":"6","key":"2022100306594699400_CIT0004","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1016\/j.cell.2017.02.025","article-title":"Complement component 3 adapts the cerebrospinal fluid for leptomeningeal metastasis","volume":"168","author":"Boire","year":"2017","journal-title":"Cell"},{"issue":"6501","key":"2022100306594699400_CIT0005","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1126\/science.aaz2193","article-title":"Cancer cells deploy lipocalin-2 to collect limiting iron in leptomeningeal metastasis","volume":"369","author":"Chi","year":"2020","journal-title":"Science"},{"issue":"14","key":"2022100306594699400_CIT0006","doi-asserted-by":"crossref","first-page":"4109","DOI":"10.1158\/1078-0432.CCR-21-1694","article-title":"Single-cell characterization of the immune microenvironment of melanoma brain and leptomeningeal metastases","volume":"27","author":"Smalley","year":"2021","journal-title":"Clin Cancer Res."},{"issue":"12","key":"2022100306594699400_CIT0007","doi-asserted-by":"crossref","first-page":"2411","DOI":"10.1158\/0008-5472.CAN-15-0145","article-title":"Ex vivo culture of CTCs: an emerging resource to guide cancer therapy","volume":"75","author":"Maheswaran","year":"2015","journal-title":"Cancer Res."},{"issue":"4","key":"2022100306594699400_CIT0008","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1016\/j.biotechadv.2018.03.007","article-title":"Circulating tumor cell isolation, culture, and downstream molecular analysis","volume":"36","author":"Sharma","year":"2018","journal-title":"Biotechnol Adv."},{"issue":"6193","key":"2022100306594699400_CIT0009","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1126\/science.1253533","article-title":"Cancer therapy. Ex vivo culture of circulating breast tumor cells for individualized testing of drug susceptibility","volume":"345","author":"Yu","year":"2014","journal-title":"Science"},{"issue":"2","key":"2022100306594699400_CIT0010","doi-asserted-by":"crossref","first-page":"2705","DOI":"10.18632\/oncotarget.23597","article-title":"Clinical significance of detecting CSF-derived tumor cells in breast cancer patients with leptomeningeal metastasis","volume":"9","author":"Li","year":"2018","journal-title":"Oncotarget"},{"issue":"5","key":"2022100306594699400_CIT0011","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1097\/CMR.0000000000000274","article-title":"A rare case of leptomeningeal carcinomatosis in a patient with uveal melanoma: case report and review of literature","volume":"26","author":"Fedorenko","year":"2016","journal-title":"Melanoma 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