{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T16:00:14Z","timestamp":1781712014399,"version":"3.54.5"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T00:00:00Z","timestamp":1768176000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Pancreatic ductal adenocarcinoma (PDAC) exhibits high lethality due to late diagnosis, therapy resistance, and cancer stem cell (CSC)-driven progression. However, the molecular determinants of stemness in PDAC remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We integrated RNA-sequencing and clinical data from TCGA to calculate stemness indices and identify hub genes using weighted co-expression network analysis and differential expression profiling. PCDH1 expression was validated in PDAC tissues by qRT-PCR and immunohistochemistry. Functional assays, including MTT, colony formation, Transwell, wound healing, flow cytometry, and spheroid culture, were performed following PCDH1 knockdown. Transcriptome sequencing was used to delineate downstream signaling mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>PCDH1 emerged as a stemness-associated oncogene strongly linked to poor survival. It was markedly overexpressed in PDAC tissues and cell lines. Silencing PCDH1 significantly impaired proliferation, clonogenicity, migration, and CSC frequency. Sphere-forming ability was also reduced. Transcriptomic analysis revealed downregulation of PI3K\/AKT signaling upon PCDH1 knockdown, and rescue experiments confirmed its role in driving PDAC progression through PI3K\/AKT activation. High PCDH1 expression further correlated with immune exclusion and distinctive patterns of chemosensitivity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>PCDH1 is a novel stemness-linked oncogene that accelerates PDAC progression via PI3K\/AKT signaling. Its prognostic relevance, association with immune evasion, and impact on drug responsiveness highlight PCDH1 as a promising biomarker and therapeutic target for CSC-directed intervention in PDAC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2025.1696695","type":"journal-article","created":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T05:42:06Z","timestamp":1768196526000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["PCDH1 facilitates migration, proliferation, and stemness of pancreatic cancer cells through PI3K-Akt signaling"],"prefix":"10.3389","volume":"15","author":[{"given":"Zhiqiang","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhipeng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuang","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weihui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dali","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3390\/cells11193068","article-title":"Pancreatic ductal adenocarcinoma: molecular pathology and predictive biomarkers","volume":"11","author":"Taherian","year":"2022","journal-title":"Cells"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.suronc.2022.101844","article-title":"Role of genetic testing in hepatic, pancreatic, and biliary cancers","volume":"44","author":"Hewitt","year":"2022","journal-title":"Surg Oncol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(04)15841-8","article-title":"Pancreatic cancer","volume":"363","author":"Li","year":"2004","journal-title":"Lancet"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1080\/14656566.2022.2149322","article-title":"Pharmacotherapeutic options for pancreatic ductal adenocarcinoma","volume":"23","author":"Sardar","year":"2022","journal-title":"Expert Opin Pharmacother"},{"key":"B5","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1200\/op.22.00328","article-title":"Pancreatic adenocarcinoma management","volume":"19","author":"Jiang","year":"2023","journal-title":"JCO Oncol Pract"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3390\/diagnostics13020215","article-title":"Current status of the diagnosis of early-stage pancreatic ductal adenocarcinoma","volume":"13","author":"Nakaoka","year":"2023","journal-title":"Diagnostics (Basel)"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1746.2011.07015.x","article-title":"Biological and clinical relevance of stem cells in pancreatic adenocarcinoma","author":"Rasheed","year":"2012","journal-title":"J Gastroenterol Hepatol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1155\/2017\/5619472","article-title":"Stemness in cancer: stem cells, cancer stem cells, and their microenvironment","volume":"2017","author":"Aponte","year":"2017","journal-title":"Stem Cells Int"},{"key":"B9","doi-asserted-by":"publisher","first-page":"165424","DOI":"10.1016\/j.bbadis.2019.02.019","article-title":"Cancer cells stemness: A doorstep to targeted therapy","volume":"1866","author":"Prasad","year":"2020","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"key":"B10","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1186\/s12943-017-0595-x","article-title":"Cancer stem cell niche models and contribution by mesenchymal stroma\/stem cells","volume":"16","author":"Melzer","year":"2017","journal-title":"Mol Cancer"},{"key":"B11","doi-asserted-by":"publisher","first-page":"970","DOI":"10.3390\/cancers14040970","article-title":"Intrinsic and extrinsic factors impacting cancer stemness and tumor progression","volume":"14","author":"Ponomarev","year":"2022","journal-title":"Cancers (Basel)"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.60641","article-title":"The interplay between M6a modification and non-coding rna in cancer stemness modulation: mechanisms, signaling pathways, and clinical implications","volume":"17","author":"Qin","year":"2021","journal-title":"Int J Biol Sci"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.641498","article-title":"Regulation of formation, stemness and therapeutic resistance of cancer stem cells","volume":"9","author":"Jing","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1016\/j.cell.2018.03.034","article-title":"Machine learning identifies stemness features associated with oncogenic dedifferentiation","volume":"173","author":"Malta","year":"2018","journal-title":"Cell"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky311","article-title":"Genemania update 2018","volume":"46","author":"Franz","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa1020","article-title":"Tisch: A comprehensive web resource enabling interactive single-cell transcriptome visualization of tumor microenvironment","volume":"49","author":"Sun","year":"2021","journal-title":"Nucleic Acids Res"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bty411","article-title":"Gscalite: A web server for gene set cancer analysis","volume":"34","author":"Liu","year":"2018","journal-title":"Bioinformatics"},{"key":"B18","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/0022-1759(83)90303-4","article-title":"Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays","volume":"65","author":"Mosmann","year":"1983","journal-title":"J Immunol Methods"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2006.339","article-title":"Clonogenic assay of cells in vitro","volume":"1","author":"Franken","year":"2006","journal-title":"Nat Protoc"},{"key":"B20","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.mrrev.2012.08.001","article-title":"In vitro cell migration and invasion assays","volume":"752","author":"Kramer","year":"2013","journal-title":"Mutat Res"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2007.30","article-title":"In vitro scratch assay: A convenient and inexpensive method for analysis of cell migration in vitro","volume":"2","author":"Liang","year":"2007","journal-title":"Nat Protoc"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.neo.2014.12.004","article-title":"Spherical cancer models in tumor biology","volume":"17","author":"Weiswald","year":"2015","journal-title":"Neoplasia"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3390\/jcm11164866","article-title":"Advances and remaining challenges in the treatment for borderline resectable and locally advanced pancreatic ductal adenocarcinoma","volume":"11","author":"Sulciner","year":"2022","journal-title":"J Clin Med"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistics 2020: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J Clin"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pathmechdis.3.121806.154305","article-title":"Pancreatic cancer","volume":"3","author":"Maitra","year":"2008","journal-title":"Annu Rev Pathol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra0901557","article-title":"Pancreatic cancer","volume":"362","author":"Hidalgo","year":"2010","journal-title":"N Engl J Med"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/367645a0","article-title":"A Cell Initiating Human Acute Myeloid Leukaemia after Transplantation into Scid Mice","volume":"367","author":"Lapidot","year":"1994","journal-title":"Nature"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.Can-06-2030","article-title":"Identification of pancreatic cancer stem cells","volume":"67","author":"Li","year":"2007","journal-title":"Cancer Res"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1096\/fj.11-185207","article-title":"Characterization of protocadherin-1 expression in primary bronchial epithelial cells: association with epithelial cell differentiation","volume":"26","author":"Koning","year":"2012","journal-title":"FASEB J"},{"key":"B30","doi-asserted-by":"publisher","first-page":"792","DOI":"10.1183\/09031936.00021613","article-title":"The pcdh1 gene and asthma in early childhood","volume":"43","author":"Mortensen","year":"2014","journal-title":"Eur Respir J"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200810-1621OC","article-title":"Identification of pcdh1 as a novel susceptibility gene for bronchial hyperresponsiveness","volume":"180","author":"Koppelman","year":"2009","journal-title":"Am J Respir Crit Care Med"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2018.08.007","article-title":"Pancreatic cancer stem cells: A state or an entity","volume":"53","author":"Hermann","year":"2018","journal-title":"Semin Cancer Biol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3390\/cancers11050732","article-title":"Targeting cancer stem cells: A strategy for effective eradication of cancer","volume":"11","author":"Shibata","year":"2019","journal-title":"Cancers (Basel)"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2020.09.008","article-title":"Molecular therapeutics of pancreatic ductal adenocarcinoma: targeted pathways and the role of cancer stem cells","volume":"41","author":"Stoica","year":"2020","journal-title":"Trends Pharmacol Sci"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1102","DOI":"10.1186\/s12885-023-11474-1","article-title":"Pcdh1, a poor prognostic biomarker and potential target for pancreatic adenocarcinoma metastatic therapy","volume":"23","author":"Du","year":"2023","journal-title":"BMC Cancer"},{"key":"B36","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1038\/s41419-022-05087-y","article-title":"Pcdh1 promotes progression of pancreatic ductal adenocarcinoma via activation of nf-\u039ab signalling by interacting with kpnb1","volume":"13","author":"Ye","year":"2022","journal-title":"Cell Death Dis"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1002\/stem.2114","article-title":"Concise review: stem cells in pancreatic cancer: from concept to translation","volume":"33","author":"Raj","year":"2015","journal-title":"Stem Cells"},{"key":"B38","doi-asserted-by":"publisher","first-page":"97","DOI":"10.4161\/cam.5.2.14374","article-title":"Non-clustered protocadherin","volume":"5","author":"Kim","year":"2011","journal-title":"Cell Adh Migr"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2014.02.002","article-title":"Metastatic stem cells: sources, niches, and vital pathways","volume":"14","author":"Oskarsson","year":"2014","journal-title":"Cell Stem Cell"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/s0955-0674(02)00365-4","article-title":"Protocadherins","volume":"14","author":"Frank","year":"2002","journal-title":"Curr Opin Cell Biol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3390\/cells8080926","article-title":"Cancer stem cells and targeting strategies","volume":"8","author":"Barbato","year":"2019","journal-title":"Cells"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2022.216007","article-title":"Engaging stemness improves cancer immunotherapy","volume":"554","author":"Dianat-Moghadam","year":"2023","journal-title":"Cancer Lett"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2025.1696695\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T05:42:08Z","timestamp":1768196528000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2025.1696695\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,12]]},"references-count":42,"alternative-id":["10.3389\/fonc.2025.1696695"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2025.1696695","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,12]]},"article-number":"1696695"}}