{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T03:13:35Z","timestamp":1787022815598,"version":"build-2736575974"},"reference-count":32,"publisher":"Bioscientifica","issue":"12","content-domain":{"domain":["journals.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,12,1]]},"abstract":"<jats:p>Primary cilia have emerged as key regulators in cancer biology, influencing tumor progression and therapeutic response through diverse signaling pathways. In this study, we identify WDR60, a component of the dynein-2 complex essential for retrograde intraflagellar transport, as a novel modulator of pancreatic neuroendocrine tumor (Pa-NET) behavior. Transcriptomic analysis of the GEO dataset GSE73338 revealed that WDR60 is significantly upregulated in both primary and metastatic Pa-NETs compared to normal pancreatic islets. Moreover, WDR60 expression is higher in G2 compared to G1 Pa-NETs. Functional analyses in QGP-1 cells following WDR60 silencing demonstrated broad transcriptional reprogramming with enrichment of pathways related to cell adhesion and extracellular matrix (ECM) remodeling. Notably, WDR60 knockdown reduced cell migration and enhanced adhesion without affecting cell viability or proliferation. Among the key upregulated genes were PIK3AP1, RAP1B, and RFLNA, suggesting that WDR60 is involved in regulating PI3K\/AKT signaling and cytoskeletal dynamics. To explore potential therapeutic implications, we examined the effects of Ciliobrevin A (HPI-04), an inhibitor of Hedgehog signaling and ciliogenesis. HPI-04 significantly reduced WDR60 expression, impaired cell migration, and increased adhesion. RT-qPCR confirmed overlapping gene expression changes between HPI-04 treatment and WDR60 silencing, although some differences, such as CD164 regulation, suggest WDR60-independent mechanisms. Collectively, these findings identify WDR60 as a critical regulator of cell motility and adhesion in Pa-NETs via ciliary signaling and cytoskeletal remodeling. They also support the therapeutic potential of targeting cilia-associated pathways, including WDR60 and Hedgehog signaling, in the treatment of Pa-NETs.<\/jats:p>","DOI":"10.1530\/erc-25-0218","type":"journal-article","created":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T17:05:09Z","timestamp":1763744709000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-8","source":"Crossref","is-referenced-by-count":1,"title":["Ciliogenesis in pancreatic neuroendocrine tumors: insight into the role of WDR60"],"prefix":"10.1530","volume":"32","author":[{"given":"Cristina","family":"Grassi","sequence":"first","affiliation":[{"name":"1"},{"name":"2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Laffi","sequence":"additional","affiliation":[{"name":"3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Zerbi","sequence":"additional","affiliation":[{"name":"2"},{"name":"4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Lavezzi","sequence":"additional","affiliation":[{"name":"5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5458-701X","authenticated-orcid":true,"given":"Gherardo","family":"Mazziotti","sequence":"additional","affiliation":[{"name":"2"},{"name":"5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Uccella","sequence":"additional","affiliation":[{"name":"2"},{"name":"6"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5380-2141","authenticated-orcid":true,"given":"Andrea Gerardo","family":"Lania","sequence":"additional","affiliation":[{"name":"2"},{"name":"5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1827-0530","authenticated-orcid":true,"given":"Eleonora","family":"Vitali","sequence":"additional","affiliation":[{"name":"1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","published-online":{"date-parts":[[2025,11,21]]},"reference":[{"key":"2026070909465739600_bib1","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.1038\/s41388-025-03416-x","article-title":"Primary cilia and cancer: a tale of many faces","volume":"44","author":"Collinson","year":"2025","journal-title":"Oncogene"},{"key":"2026070909465739600_bib2","doi-asserted-by":"crossref","DOI":"10.1101\/2021.09.19.459328","article-title":"WDR60-mediated dynein-2 loading into cilia powers retrograde IFT and transition zone crossing","volume":"221","author":"De-Castro","year":"2021","journal-title":"J Cell Biol"},{"key":"2026070909465739600_bib3","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1007\/s40265-016-0596-x","article-title":"Venetoclax: first global approval","volume":"76","author":"Deeks","year":"2016","journal-title":"Drugs"},{"key":"2026070909465739600_bib4","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1016\/j.humpath.2013.11.017","article-title":"Presence of primary cilia in cancer cells correlates with prognosis of pancreatic ductal adenocarcinoma","volume":"45","author":"Emoto","year":"2014","journal-title":"Hum Pathol"},{"key":"2026070909465739600_bib5","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1677\/ERC-07-0108","article-title":"Snail and Sonic Hedgehog activation in neuroendocrine tumors of the ileum","volume":"14","author":"Fendrich","year":"2007","journal-title":"Endocr Relat Cancer"},{"key":"2026070909465739600_bib6","doi-asserted-by":"crossref","first-page":"1224","DOI":"10.1016\/j.chembiol.2020.07.018","article-title":"Targeting primary ciliogenesis with small-molecule inhibitors","volume":"27","author":"Guen","year":"2020","journal-title":"Cell Chem Biol"},{"key":"2026070909465739600_bib7","doi-asserted-by":"crossref","first-page":"1628","DOI":"10.1091\/mbc.E18-03-0173","article-title":"Interaction of WDR60 intermediate chain with TCTEX1D2 light chain of the dynein-2 complex is crucial for ciliary protein trafficking","volume":"29","author":"Hamada","year":"2018","journal-title":"Mol Biol Cell"},{"key":"2026070909465739600_bib8","article-title":"Targeting PI3K\/Akt signal transduction for cancer therapy","volume":"6","author":"He","year":"2021","journal-title":"Signal Transduct Targeted Ther"},{"key":"2026070909465739600_bib9","first-page":"3041","article-title":"Primary cilia and their role in cancer (Review)","volume":"17","author":"Higgins","year":"2019","journal-title":"Oncol Lett"},{"key":"2026070909465739600_bib10","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1007\/s10930-018-9785-7","article-title":"WD40 repeat proteins: signalling scaffold with diverse functions","volume":"37","author":"Jain","year":"2018","journal-title":"Protein J"},{"key":"2026070909465739600_bib11","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1038\/nrm2804","article-title":"Regulators of the cytoplasmic dynein motor","volume":"10","author":"Kardon","year":"2009","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2026070909465739600_bib32","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1016\/j.cell.2020.10.023","article-title":"An organoid biobank of neuroendocrine neoplasms enables genotype-phenotype mapping","volume":"183","author":"Kawasaki","year":"2020","journal-title":"Cell"},{"key":"2026070909465739600_bib12","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1038\/s41568-018-0023-6","article-title":"Ciliary signalling in cancer","volume":"18","author":"Liu","year":"2018","journal-title":"Nat Rev Cancer"},{"key":"2026070909465739600_bib13","doi-asserted-by":"crossref","DOI":"10.1016\/j.modpat.2024.100475","article-title":"Primary cilia as a tumor marker in pituitary neuroendocrine tumors","volume":"37","author":"Mart\u00ednez-Hern\u00e1ndez","year":"2024","journal-title":"Mod Pathol"},{"key":"2026070909465739600_bib14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3390\/cancers14194769","article-title":"Therapy resistant gastroenteropancreatic neuroendocrine tumors","volume":"14","author":"McClellan","year":"2022","journal-title":"Cancers"},{"key":"2026070909465739600_bib15","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1200\/JCO.2008.21.5988","article-title":"Pancreatic endocrine tumors: expression profiling evidences a role for AKT-mTOR pathway","volume":"28","author":"Missiaglia","year":"2010","journal-title":"J Clin Oncol"},{"key":"2026070909465739600_bib16","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1093\/jb\/mvx087","article-title":"Ciliary protein trafficking mediated by IFT and BBSome complexes with the aid of kinesin-2 and dynein-2 motors","volume":"163","author":"Nakayama","year":"2018","journal-title":"J Biochem"},{"key":"2026070909465739600_bib17","doi-asserted-by":"crossref","DOI":"10.1002\/advs.201801138","article-title":"Primary cilia as signaling hubs in health and disease","volume":"6","author":"Nishimura","year":"2019","journal-title":"Adv Sci"},{"key":"2026070909465739600_bib18","doi-asserted-by":"crossref","first-page":"4947","DOI":"10.3390\/ijms20194947","article-title":"Extracellular matrix alterations in metastatic processes","volume":"20","author":"Paolillo","year":"2019","journal-title":"Int J Mol Sci"},{"key":"2026070909465739600_bib19","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/s12022-022-09708-2","article-title":"Overview of the 2022 WHO classification of neuroendocrine neoplasms","volume":"33","author":"Rindi","year":"2022","journal-title":"Endocr Pathol"},{"key":"2026070909465739600_bib20","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1038\/nrd.2017.179","article-title":"WD40 repeat domain proteins: a novel target class?","volume":"16","author":"Schapira","year":"2017","journal-title":"Nat Rev Drug Discov"},{"key":"2026070909465739600_bib21","doi-asserted-by":"crossref","first-page":"1530","DOI":"10.4161\/cbt.5.11.3458","article-title":"Sonic Hedgehog-Gli1 signaling pathway might become an effective therapeutic target in gastrointestinal neuroendocrine carcinomas","volume":"5","author":"Shida","year":"2006","journal-title":"Cancer Biol Ther"},{"key":"2026070909465739600_bib22","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/bs.ircmb.2024.01.003","article-title":"Therapeutic potential of Hedgehog signaling in advanced cancer types","volume":"386","author":"Singh","year":"2024","journal-title":"Int Rev Cell Mol Biol"},{"key":"2026070909465739600_bib23","doi-asserted-by":"crossref","DOI":"10.3389\/fcell.2020.622822","article-title":"Primary cilia, ciliogenesis and the actin cytoskeleton: a little less resorption, a little more actin please","volume":"8","author":"Smith","year":"2020","journal-title":"Front Cell Dev Biol"},{"key":"2026070909465739600_bib24","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1007\/s11864-017-0514-9","article-title":"Update in the therapy of advanced neuroendocrine tumors","volume":"18","author":"Uri","year":"2017","journal-title":"Curr Treat Options Oncol"},{"key":"2026070909465739600_bib25","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1530\/ERC-15-0358","article-title":"Filamin-A is required to mediate SST2 effects in pancreatic neuroendocrine tumours","volume":"23","author":"Vitali","year":"2016","journal-title":"Endocr Relat Cancer"},{"key":"2026070909465739600_bib26","doi-asserted-by":"crossref","first-page":"77330","DOI":"10.18632\/oncotarget.20473","article-title":"FLNA is implicated in pulmonary neuroendocrine tumors aggressiveness and progression","volume":"8","author":"Vitali","year":"2017","journal-title":"Oncotarget"},{"key":"2026070909465739600_bib27","doi-asserted-by":"crossref","DOI":"10.1016\/j.mce.2020.110803","article-title":"A novel insight into the anticancer mechanism of metformin in pancreatic neuroendocrine tumor cells","volume":"509","author":"Vitali","year":"2020","journal-title":"Mol Cell Endocrinol"},{"key":"2026070909465739600_bib28","doi-asserted-by":"crossref","first-page":"3207","DOI":"10.1002\/jcp.30117","article-title":"Functional aspects of primary cilium in signaling, assembly and microenvironment in cancer","volume":"236","author":"Wang","year":"2021","journal-title":"J Cell Physiol"},{"key":"2026070909465739600_bib29","first-page":"1","article-title":"Intraflagellar transport proteins as regulators of primary cilia length","volume":"9","author":"Wang","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"2026070909465739600_bib30","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"ClusterProfiler: an R package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"OMICS A J Integr Biol"},{"key":"2026070909465739600_bib31","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.1002\/ijc.31736","article-title":"Clinical significance and biological function of WD repeat domain 54 as an oncogene in colorectal cancer","volume":"144","author":"Yuan","year":"2019","journal-title":"Int J Cancer"}],"container-title":["Endocrine-Related Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/erc.bioscientifica.com\/view\/journals\/erc\/32\/12\/ERC-25-0218.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/erc.bioscientifica.com\/downloadpdf\/journals\/erc\/32\/12\/ERC-25-0218.xml","content-type":"text\/html","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.bioscientifica.com\/erc\/article-pdf\/doi\/10.1530\/ERC-25-0218\/505952\/erc-25-0218.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.bioscientifica.com\/erc\/article-pdf\/doi\/10.1530\/ERC-25-0218\/505952\/erc-25-0218.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T13:47:05Z","timestamp":1783604825000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.bioscientifica.com\/erc\/article\/32\/12\/e250218\/75910\/Ciliogenesis-in-pancreatic-neuroendocrine-tumors"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,21]]},"references-count":32,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,12,1]]}},"URL":"https:\/\/doi.org\/10.1530\/erc-25-0218","relation":{},"ISSN":["1479-6821","1351-0088"],"issn-type":[{"value":"1479-6821","type":"electronic"},{"value":"1351-0088","type":"print"}],"subject":[],"published":{"date-parts":[[2025,11,21]]},"article-number":"e250218"}}