{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T17:29:20Z","timestamp":1788456560397,"version":"build-2803163510"},"reference-count":112,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2021,3,9]],"date-time":"2021-03-09T00:00:00Z","timestamp":1615248000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01DK080730"],"award-info":[{"award-number":["R01DK080730"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01MH106522"],"award-info":[{"award-number":["R01MH106522"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,4,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Pancreatic ductal adenocarcinoma (PDAC) is an aggressive form of cancer with high mortality. The cellular origins of PDAC are largely unknown; however, ductal cells, especially centroacinar cells (CACs), have several characteristics in common with PDAC, such as expression of SOX9 and components of the Notch-signaling pathway. Mutations in KRAS and alterations to Notch signaling are common in PDAC, and both these pathways regulate the transcription factor SOX9. To identify genes regulated by SOX9, we performed siRNA knockdown of SOX9 followed by RNA-seq in PANC-1s, a human PDAC cell line. We report 93 differentially expressed (DE) genes, with convergence on alterations to Notch-signaling pathways and ciliogenesis. These results point to SOX9 and Notch activity being in a positive feedback loop and SOX9 regulating cilia production in PDAC. We additionally performed ChIP-seq in PANC-1s to identify direct targets of SOX9 binding and integrated these results with our DE gene list. Nine of the top 10 downregulated genes have evidence of direct SOX9 binding at their promoter regions. One of these targets was the cancer stem cell marker EpCAM. Using whole-mount in situ hybridization to detect epcam transcript in zebrafish larvae, we demonstrated that epcam is a CAC marker and that Sox9 regulation of epcam expression is conserved in zebrafish. Additionally, we generated an epcam null mutant and observed pronounced defects in ciliogenesis during development. Our results provide a link between SOX9, EpCAM and ciliary repression that can be exploited in improving our understanding of the cellular origins and mechanisms of PDAC.<\/jats:p>","DOI":"10.1093\/hmg\/ddab064","type":"journal-article","created":{"date-parts":[[2021,2,25]],"date-time":"2021-02-25T20:12:40Z","timestamp":1614283960000},"page":"485-499","source":"Crossref","is-referenced-by-count":14,"title":["SOX9 modulates cancer biomarker and cilia genes in pancreatic cancer"],"prefix":"10.1093","volume":"30","author":[{"given":"Hannah E","family":"Edelman","sequence":"first","affiliation":[{"name":"McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, 470 Miller Research Building, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah A","family":"McClymont","sequence":"additional","affiliation":[{"name":"McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, 470 Miller Research Building, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tori R","family":"Tucker","sequence":"additional","affiliation":[{"name":"Department of Developmental and Cell Biology, University of California, Irvine, Natural Sciences II, CA 92697, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santiago","family":"Pineda","sequence":"additional","affiliation":[{"name":"Department of Developmental and Cell Biology, University of California, Irvine, Natural Sciences II, CA 92697, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca L","family":"Beer","sequence":"additional","affiliation":[{"name":"McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, 470 Miller Research Building, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew S","family":"McCallion","sequence":"additional","affiliation":[{"name":"McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, 470 Miller Research Building, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J","family":"Parsons","sequence":"additional","affiliation":[{"name":"McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, 470 Miller Research Building, Baltimore, MD 21205, USA"},{"name":"Department of Developmental and Cell Biology, University of California, Irvine, Natural Sciences II, CA 92697, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,3,9]]},"reference":[{"key":"2021050613570062900_ref1","volume-title":"Cancer Facts & Figures 2020","author":"American Cancer Society","year":"2020"},{"key":"2021050613570062900_ref2","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1002\/1097-0142(19951101)76:9<1671::AID-CNCR2820760926>3.0.CO;2-R","article-title":"The National Cancer Data Base report on pancreatic cancer","volume":"76","author":"Niederhuber","year":"1995","journal-title":"Cancer"},{"key":"2021050613570062900_ref3","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.cell.2011.11.025","article-title":"EMT and dissemination precede pancreatic tumor formation","volume":"148","author":"Rhim","year":"2012","journal-title":"Cell"},{"key":"2021050613570062900_ref4","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.jbior.2017.11.007","article-title":"Molecular and cellular mechanisms of chemoresistance in pancreatic cancer","volume":"68","author":"Adamska","year":"2018","journal-title":"Adv Biol Regul"},{"key":"2021050613570062900_ref5","doi-asserted-by":"crossref","first-page":"4282","DOI":"10.1038\/onc.2015.441","article-title":"p53 mutations cooperate with oncogenic Kras to promote adenocarcinoma from pancreatic ductal cells","volume":"35","author":"Bailey","year":"2016","journal-title":"Oncogene"},{"key":"2021050613570062900_ref6","doi-asserted-by":"crossref","first-page":"3112","DOI":"10.1101\/gad.1158703","article-title":"Activated Kras and Ink4a\/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma","volume":"17","author":"Aguirre","year":"2003","journal-title":"Genes Dev."},{"key":"2021050613570062900_ref7","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1136\/gutjnl-2017-314426","article-title":"Cell of origin affects tumour development and phenotype in pancreatic ductal adenocarcinoma","volume":"68","author":"Lee","year":"2019","journal-title":"Gut"},{"key":"2021050613570062900_ref8","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.ydbio.2016.02.027","article-title":"Centroacinar cells: at the center of pancreas regeneration","volume":"413","author":"Beer","year":"2016","journal-title":"Dev. 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