{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T13:04:32Z","timestamp":1784898272348,"version":"3.55.0"},"reference-count":71,"publisher":"American Society for Clinical Investigation","issue":"14","license":[{"start":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T00:00:00Z","timestamp":1784678400000},"content-version":"vor","delay-in-days":50,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["NIH\/NHLBI-HL167137-01"],"award-info":[{"award-number":["NIH\/NHLBI-HL167137-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Tuberous Sclerosis Alliance","award":["990240"],"award-info":[{"award-number":["990240"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["NIH\/NCI,P30CA013696"],"award-info":[{"award-number":["NIH\/NCI,P30CA013696"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000090","name":"Congressionally Directed Medical Research Programs","doi-asserted-by":"crossref","award":["W81XWH-18-1-0077"],"award-info":[{"award-number":["W81XWH-18-1-0077"]}],"id":[{"id":"10.13039\/100000090","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,22]]},"abstract":"<jats:p>\n                    Tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis (LAM) lack well-defined cellular origins, limiting treatment options. In this report, scRNA-seq of\n                    <jats:italic>\n                      Tsc2\n                      <jats:sup>+\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    mouse renal cystadenomas revealed an 80-fold increase in a tumor cell subpopulation with neural crest features, expressing known cranial neural crest genes as SRY box transcription factor 9 (\n                    <jats:italic>Sox9<\/jats:italic>\n                    ), transcription factor activator protein (\n                    <jats:italic>Tfap2a<\/jats:italic>\n                    ), and candidate neurocristopathy markers, osteopontin (\n                    <jats:italic>Spp1<\/jats:italic>\n                    ), lipocalin-2 (\n                    <jats:italic>Lcn2<\/jats:italic>\n                    ), clusterin (\n                    <jats:italic>Clu<\/jats:italic>\n                    ), and cytokeratin 18 (\n                    <jats:italic>Krt18<\/jats:italic>\n                    ). These signatures were validated in mouse tumors and LAM patient lesions and serum, identifying a tumor phenotype distinct from traditional VEGFD detection. Pathway analysis indicated activation of WNT\/SHH signaling, nephric duct formation, and protumorigenic signals, with transcription factor 7 (\n                    <jats:italic>Tcf7<\/jats:italic>\n                    ) and ephrin-A ligands as key upstream regulators.\n                    <jats:italic>Spp1<\/jats:italic>\n                    KO in cranial neural crest cells (CNCCs) significantly reduced proliferation (28%\u201333%), migration (54%\u201376%), and invasion (29%\u201364%) without affecting viability, while\n                    <jats:italic>Tsc2<\/jats:italic>\n                    KO increased viability 3- to 6-fold with minimal effect on chemotaxis. Elevated serum levels of SPP1 and KRT18 in 1 subset of patients with LAM, decreased LCN2 in nearly all cases, and distinct increases in VEGFD in a separate subset suggest complementary roles for these biomarkers. Overall, findings support a neurocristopathic model of tumor development in TSC and LAM and identify potential biomarkers and therapeutic targets beyond mTOR inhibition.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.195013","type":"journal-article","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T18:46:03Z","timestamp":1780598763000},"source":"Crossref","is-referenced-by-count":0,"title":["Neural crest cell signatures drive tumorigenesis in tuberous sclerosis complex and lymphangioleiomyomatosis"],"prefix":"10.1172","volume":"11","author":[{"given":"Uchenna J.","family":"Unachukwu","sequence":"first","affiliation":[{"name":"Center for LAM and Rare Lung Disease, Department of Anesthesiology, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enio B.","family":"Garcia","sequence":"additional","affiliation":[{"name":"Center for LAM and Rare Lung Disease, Department of Anesthesiology, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nooralam","family":"Rai","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (Pulmonary), Columbia University Medical Center, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6219-6083","authenticated-orcid":true,"given":"Jeanine M.","family":"D\u2019Armiento","sequence":"additional","affiliation":[{"name":"Center for LAM and Rare Lung Disease, Department of Anesthesiology, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2026,6,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15816"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1788"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)61134-9"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3390\/biom14091190"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201405-0918OC"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-154-12-201106210-00007"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.mehy.2020.109703"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201912-2445OC"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1089\/lrb.2009.0013"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2021.102684"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.06.028"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1126\/science.aas9536"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1530\/ERC-19-0431"},{"key":"B14"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-15-1287"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-40173-5"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2009-0462OC"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)64727-X"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2015.10.002"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-45308-w"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms7727"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07113-9"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3892\/ijo.2013.2015"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2013-0456OC"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20042469"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1097\/JS9.0000000000002589"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2020.12.012"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2023.08.001"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2025-0237OC"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.23869"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsb.2013.05.022"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1002\/ctm2.1515"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1177\/10104283241313441"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1136\/thoraxjnl-2022-218772"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1378\/chest.10-0573"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1089\/scd.2012.0155"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2020.03.005"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-03512-5"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1211747110"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1101\/gad.240102"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.2015.153"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2021.01.018"},{"issue":"4","key":"B43","first-page":"3871","article-title":"SOX9 was involved in TKIs resistance in renal cell carcinoma via Raf\/MEK\/ERK signaling pathway","volume":"8","author":"Li","year":"2015","journal-title":"Int J Clin Exp Pathol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.19198"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2015.10.015"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2017.04.014"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1530\/ERC-23-0312"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201612069"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/bs.ctdb.2014.11.005"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.3390\/cells8101173"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-025-02649-3"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2019.00090"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-023-04189-1"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-17358-3"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1016\/j.jprot.2018.02.010"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1016\/j.tranon.2026.102682"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1186\/s40164-025-00647-2"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-018-0142-z"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-024-00839-5"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1378\/chest.08-1160"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2026.189555"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201607-1384ST"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.673599"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-25-1486"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbaf207"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-22-0224"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.5TA0814-373"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbab337"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt703"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.3791\/58346"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.3791\/51046"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/195013\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T12:34:20Z","timestamp":1784896460000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/195013"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,2]]},"references-count":71,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7,22]]},"published-print":{"date-parts":[[2026,7,22]]}},"alternative-id":["10.1172\/jci.insight.195013"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.195013","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,2]]},"article-number":"e195013"}}