{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T16:05:59Z","timestamp":1764345959002,"version":"3.46.0"},"reference-count":54,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T00:00:00Z","timestamp":1764288000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T00:00:00Z","timestamp":1764288000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82473308","82373365","82472991","82203423","82403771","82103672","82173317"],"award-info":[{"award-number":["82473308","82373365","82472991","82203423","82403771","82103672","82173317"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Scientific and Technological Projects of Tianjin"},{"DOI":"10.13039\/501100006606","name":"Natural Science Foundation of Tianjin","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100006606","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Tianjin Health Science and Technology Project"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Intrahepatic cholangiocarcinoma (ICC) is a distinct and increasingly prevalent subtype of cholangiocarcinoma arising from the epithelial cells of the intrahepatic bile ducts. Its molecular diversity contributes to its highly aggressive nature and resistance to chemotherapy. SVEP1 (sushi, Von Willebrand factor type A, EGF, and pentaxin) is a multi-domain extracellular matrix (ECM) protein that is vital for embryogenesis, cell-cell adhesion, and the maintenance of epidermal differentiation. However, the specific effect of SVEP1 on the occurrence and progression of ICC remains poorly understood. Therefore, this study aims to examine the role of SVEP1 in ICC. We first identified SVEP1 using high-throughput RNA sequencing in two groups of patients with ICC with different disease-free survival rates. We further analyzed the expression pattern of SVEP1 in ICC using various public datasets and clinical tissue samples, exploring the correlation between SVEP1 depletion and ICC clinical prognosis. The regulatory role of SVEP1 depletion in ICC progression was studied using in vitro and in vivo experiments. We found that decreased SVEP1 expression positively correlates with early recurrence and shorter overall survival in ICC. Moreover, SVEP1 downregulation was correlated with multiple poor prognostic parameters, including positive lymph nodes, satellite nodes, and high Ki-67 expression. Downregulated SVEP1 expression promoted ICC cell proliferation, chemotactic migration, and invasion in vitro, as well as tumor growth and lung metastasis in vivo. These effects were mediated by EMT phenotype switching through the activation of the Jag2\/Notch1\/Hes5 pathway. Our findings enhance the understanding of the novel mechanisms driving ICC progression and metastasis, suggesting that SVEP1 is a potential biomarker for ICC diagnosis.<\/jats:p>","DOI":"10.1038\/s41419-025-08170-2","type":"journal-article","created":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T15:09:44Z","timestamp":1764342584000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Low SVEP1 in intrahepatic cholangiocarcinoma mediates phenotype switching-driven metastasis by Jag2\/Notch1\/Hes5"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9490-7671","authenticated-orcid":false,"given":"Lu","family":"Chen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8414-2046","authenticated-orcid":false,"given":"Zhiqiang","family":"Han","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiangdong","family":"Tian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kangwei","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenchen","family":"Gong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yun","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yimeng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuren","family":"Xia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peipei","family":"Song","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Tang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norihiro","family":"Kokudo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liwei","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Luo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuchao","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5979-5213","authenticated-orcid":false,"given":"Tianqiang","family":"Song","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3345-8005","authenticated-orcid":false,"given":"Hua","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,11,28]]},"reference":[{"key":"8170_CR1","first-page":"209","volume":"71","author":"H Sung","year":"2021","unstructured":"Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209\u201349.","journal-title":"CA Cancer J Clin"},{"key":"8170_CR2","doi-asserted-by":"publisher","first-page":"3108","DOI":"10.3390\/jcm10143108","volume":"10","author":"T Sasaki","year":"2021","unstructured":"Sasaki T, Takeda T, Okamoto T, Ozaka M, Sasahira N. Chemotherapy for biliary tract cancer in 2021. J Clin Med. 2021;10:3108.","journal-title":"J Clin Med"},{"key":"8170_CR3","volume":"1","author":"M Feng","year":"2020","unstructured":"Feng M, Pan Y, Kong R, Shu S. Therapy of primary liver cancer. Innovation. 2020;1:100032.","journal-title":"Innovation"},{"key":"8170_CR4","first-page":"198","volume":"73","author":"D Moris","year":"2023","unstructured":"Moris D, Palta M, Kim C, Allen PJ, Morse MA, Lidsky ME. Advances in the treatment of intrahepatic cholangiocarcinoma: An overview of the current and future therapeutic landscape for clinicians. CA Cancer J Clin. 2023;73:198\u2013222.","journal-title":"CA Cancer J Clin"},{"key":"8170_CR5","doi-asserted-by":"publisher","first-page":"170","DOI":"10.35772\/ghm.2024.01002","volume":"6","author":"N Kokudo","year":"2024","unstructured":"Kokudo N, Kokudo T, Song P, Tang W. Role of liver resection in the era of advanced systemic therapy for hepatocellular carcinoma. Glob Health Med. 2024;6:170\u20133.","journal-title":"Glob Health Med"},{"key":"8170_CR6","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1038\/s41568-023-00656-5","volume":"24","author":"E Cambria","year":"2024","unstructured":"Cambria E, Coughlin MF, Floryan MA, Offeddu GS, Shelton SE, Kamm RD. Linking cell mechanical memory and cancer metastasis. Nat Rev Cancer. 2024;24:216\u201328.","journal-title":"Nat Rev Cancer"},{"key":"8170_CR7","doi-asserted-by":"publisher","first-page":"40","DOI":"10.35772\/ghm.2022.01059","volume":"5","author":"Y Toyoshima","year":"2023","unstructured":"Toyoshima Y, Narumiya K, Kudo K, Egawa H, Hosoda K. Comparative analysis of the outcomes of gastrectomy vs. endoscopic mucosal resection or endoscopic submucosal dissection for the treatment of gastric tube cancer after esophagectomy. Glob Health Med. 2023;5:40\u20136.","journal-title":"Glob Health Med"},{"key":"8170_CR8","doi-asserted-by":"publisher","first-page":"1063","DOI":"10.1038\/s43018-023-00595-y","volume":"4","author":"A P\u00e9rez-Gonz\u00e1lez","year":"2023","unstructured":"P\u00e9rez-Gonz\u00e1lez A, B\u00e9vant K, Blanpain C. Cancer cell plasticity during tumor progression, metastasis and response to therapy. Nat Cancer. 2023;4:1063\u201382.","journal-title":"Nat Cancer"},{"key":"8170_CR9","doi-asserted-by":"crossref","unstructured":"Gong W, Zhang S, Tian X, Chen W, He Y, Chen L, et al. Tertiary lymphoid structures as a potential prognostic biomarker for combined hepatocellular-cholangiocarcinoma. Hepatol Int. 2024;18:1310\u201325.","DOI":"10.1007\/s12072-024-10694-2"},{"key":"8170_CR10","doi-asserted-by":"publisher","first-page":"932","DOI":"10.1016\/j.ccell.2019.04.007","volume":"35","author":"R Xue","year":"2019","unstructured":"Xue R, Chen L, Zhang C, Fujita M, Li R, Yan SM, et al. Genomic and transcriptomic profiling of combined hepatocellular and intrahepatic cholangiocarcinoma reveals distinct molecular subtypes. Cancer Cell. 2019;35:932\u201347.e8.","journal-title":"Cancer Cell"},{"key":"8170_CR11","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1016\/j.suronc.2020.04.017","volume":"34","author":"S Shenoy","year":"2020","unstructured":"Shenoy S. Cell plasticity in cancer: a complex interplay of genetic, epigenetic mechanisms and tumor micro-environment. Surg Oncol. 2020;34:154\u201362.","journal-title":"Surg Oncol"},{"key":"8170_CR12","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2300489120","volume":"120","author":"L Ginn","year":"2023","unstructured":"Ginn L, Maltas J, Baker MJ, Chaturvedi A, Wilson L, Guilbert R, et al. A TIAM1-TRIM28 complex mediates epigenetic silencing of protocadherins to promote migration of lung cancer cells. Proc Natl Acad Sci USA. 2023;120:e2300489120.","journal-title":"Proc Natl Acad Sci USA"},{"key":"8170_CR13","doi-asserted-by":"publisher","first-page":"89","DOI":"10.20892\/j.issn.2095-3941.2018.0077","volume":"16","author":"L Chen","year":"2019","unstructured":"Chen L, Tian X, Gong W, Sun B, Li G, Liu D, et al. Periostin mediates epithelial-mesenchymal transition through the MAPK\/ERK pathway in hepatoblastoma. Cancer Biol Med. 2019;16:89\u2013100.","journal-title":"Cancer Biol Med"},{"key":"8170_CR14","doi-asserted-by":"publisher","first-page":"3220","DOI":"10.1007\/s10620-023-07972-8","volume":"68","author":"SM Jain","year":"2023","unstructured":"Jain SM, Deka D, Das A, Paul S, Pathak S, Banerjee A. Role of interleukins in inflammation-mediated tumor immune microenvironment modulation in colorectal cancer pathogenesis. Dig Dis Sci. 2023;68:3220\u201336.","journal-title":"Dig Dis Sci"},{"key":"8170_CR15","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1002\/jcp.20497","volume":"206","author":"I Shur","year":"2006","unstructured":"Shur I, Socher R, Hameiri M, Fried A, Benayahu D. Molecular and cellular characterization of SEL-OB\/SVEP1 in osteogenic cells in vivo and in vitro. J Cell Physiol. 2006;206:420\u20137.","journal-title":"J Cell Physiol"},{"key":"8170_CR16","doi-asserted-by":"publisher","first-page":"1276","DOI":"10.1161\/CIRCRESAHA.116.308825","volume":"120","author":"N Morooka","year":"2017","unstructured":"Morooka N, Futaki S, Sato-Nishiuchi R, Nishino M, Totani Y, Shimono C, et al. Polydom is an extracellular matrix protein involved in lymphatic vessel remodeling. Circ Res. 2017;120:1276\u201388.","journal-title":"Circ Res"},{"key":"8170_CR17","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1111\/exd.13256","volume":"26","author":"L Samuelov","year":"2017","unstructured":"Samuelov L, Li Q, Bochner R, Najor NA, Albrecht L, Malchin N, et al. SVEP1 plays a crucial role in epidermal differentiation. Exp Dermatol. 2017;26:423\u201330.","journal-title":"Exp Dermatol"},{"key":"8170_CR18","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-020-2535-8","volume":"11","author":"L Chen","year":"2020","unstructured":"Chen L, Liu D, Yi X, Qi L, Tian X, Sun B, et al. The novel miR-1269b-regulated protein SVEP1 induces hepatocellular carcinoma proliferation and metastasis likely through the PI3K\/Akt pathway. Cell Death Dis. 2020;11:320.","journal-title":"Cell Death Dis"},{"key":"8170_CR19","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1053\/j.gastro.2021.08.052","volume":"162","author":"L Guo","year":"2022","unstructured":"Guo L, Yi X, Chen L, Zhang T, Guo H, Chen Z, et al. Single-cell DNA sequencing reveals punctuated and gradual clonal evolution in hepatocellular carcinoma. Gastroenterology. 2022;162:238\u201352.","journal-title":"Gastroenterology"},{"key":"8170_CR20","doi-asserted-by":"publisher","first-page":"1209","DOI":"10.4149\/neo_2022_220614N629","volume":"69","author":"WC Gong","year":"2022","unstructured":"Gong WC, Han ZQ, Guo MX, Zhao S, Guo YH, Meng B, et al. Decreased expression of SVEP1 is closely related to a cancer stem cell-like phenotype and poor prognosis in hepatocellular carcinoma. Neoplasma. 2022;69:1209\u201316.","journal-title":"Neoplasma"},{"key":"8170_CR21","doi-asserted-by":"publisher","first-page":"eabe0357","DOI":"10.1126\/scitranslmed.abe0357","volume":"13","author":"IH Jung","year":"2021","unstructured":"Jung IH, Elenbaas JS, Alisio A, Santana K, Young EP, Kang CJ, et al. SVEP1 is a human coronary artery disease locus that promotes atherosclerosis. Sci Transl Med. 2021;13:eabe0357.","journal-title":"Sci Transl Med"},{"key":"8170_CR22","doi-asserted-by":"publisher","first-page":"25615","DOI":"10.1074\/jbc.M112.355016","volume":"287","author":"R Sato-Nishiuchi","year":"2012","unstructured":"Sato-Nishiuchi R, Nakano I, Ozawa A, Sato Y, Takeichi M, Kiyozumi D, et al. Polydom\/SVEP1 is a ligand for integrin \u03b19\u03b21. J Biol Chem. 2012;287:25615\u201330.","journal-title":"J Biol Chem"},{"key":"8170_CR23","doi-asserted-by":"publisher","first-page":"1122","DOI":"10.1158\/2326-6066.CIR-20-0074","volume":"8","author":"C Spenl\u00e9","year":"2020","unstructured":"Spenl\u00e9 C, Loustau T, Murdamoothoo D, Erne W, Beghelli-de la Forest Divonne S, Veber R, et al. Tenascin-C orchestrates an immune-suppressive tumor microenvironment in oral squamous cell carcinoma. Cancer Immunol Res. 2020;8:1122\u201338.","journal-title":"Cancer Immunol Res"},{"key":"8170_CR24","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.112533","volume":"42","author":"M Saini","year":"2023","unstructured":"Saini M, Schmidleitner L, Moreno HD, Donato E, Falcone M, Bartsch JM, et al. Resistance to mesenchymal reprogramming sustains clonal propagation in metastatic breast cancer. Cell Rep. 2023;42:112533.","journal-title":"Cell Rep"},{"key":"8170_CR25","doi-asserted-by":"publisher","first-page":"1329","DOI":"10.1002\/jso.27435","volume":"128","author":"EN Kanu","year":"2023","unstructured":"Kanu EN, Rhodin KE, Masoud SJ, Eckhoff AM, Bartholomew AJ, Howell TC, et al. Tumor size and survival in intrahepatic cholangiocarcinoma treated with surgical resection or ablation. J Surg Oncol. 2023;128:1329\u201339.","journal-title":"J Surg Oncol"},{"key":"8170_CR26","doi-asserted-by":"publisher","first-page":"1540","DOI":"10.1097\/HEP.0000000000000046","volume":"77","author":"H Jeong","year":"2023","unstructured":"Jeong H, Kim KP, Jeong JH, Hwang DW, Lee JH, Kim KH, et al. Adjuvant gemcitabine plus cisplatin versus capecitabine in node-positive extrahepatic cholangiocarcinoma: the STAMP randomized trial. Hepatology. 2023;77:1540\u20139.","journal-title":"Hepatology"},{"key":"8170_CR27","doi-asserted-by":"publisher","first-page":"397","DOI":"10.5582\/bst.2021.01517","volume":"15","author":"W Zhang","year":"2022","unstructured":"Zhang W, Wang Y, Dong X, Yang B, Zhou H, Chen L, et al. Elevated serum CA19-9 indicates severe liver inflammation and worse survival after curative resection in hepatitis B-related hepatocellular carcinoma. Biosci Trends. 2022;15:397\u2013405.","journal-title":"Biosci Trends"},{"key":"8170_CR28","doi-asserted-by":"publisher","first-page":"458","DOI":"10.1111\/liv.15117","volume":"42","author":"F Tovoli","year":"2022","unstructured":"Tovoli F, Garajov\u00e1 I, Gelsomino F, Iavarone M, Federico P, Salati M, et al. Pattern of progression of intrahepatic cholangiocarcinoma: implications for second-line clinical trials. Liver Int. 2022;42:458\u201367.","journal-title":"Liver Int"},{"key":"8170_CR29","doi-asserted-by":"publisher","first-page":"688","DOI":"10.1016\/j.ejso.2023.01.006","volume":"49","author":"H Jansson","year":"2023","unstructured":"Jansson H, Villard C, Nooijen LE, Ghorbani P, Erdmann JI, Sparrelid E. Prognostic influence of multiple hepatic lesions in resectable intrahepatic cholangiocarcinoma: a systematic review and meta-analysis. Eur J Surg Oncol. 2023;49:688\u201399.","journal-title":"Eur J Surg Oncol"},{"key":"8170_CR30","doi-asserted-by":"publisher","first-page":"902","DOI":"10.1111\/hepr.13673","volume":"51","author":"S Kaneko","year":"2021","unstructured":"Kaneko S, Kurosaki M, Tsuchiya K, Yasui Y, Inada K, Kirino S, et al. Prognosis of intrahepatic cholangiocarcinoma stratified by albumin-bilirubin grade. Hepatol Res. 2021;51:902\u20138.","journal-title":"Hepatol Res"},{"key":"8170_CR31","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1002\/hep.30816","volume":"71","author":"CJ O\u2019Rourke","year":"2020","unstructured":"O\u2019Rourke CJ, Matter MS, Nepal C, Caetano-Oliveira R, Ton PT, Factor VM, et al. Identification of a pan-gamma-secretase inhibitor response signature for notch-driven cholangiocarcinoma. Hepatology. 2020;71:196\u2013213.","journal-title":"Hepatology"},{"key":"8170_CR32","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.111743","volume":"41","author":"AS Parikh","year":"2022","unstructured":"Parikh AS, Wizel A, Davis D, Lefranc-Torres A, Rodarte-Rascon AI, Miller LE, et al. Single-cell RNA sequencing identifies a paracrine interaction that may drive oncogenic notch signaling in human adenoid cystic carcinoma. Cell Rep. 2022;41:111743.","journal-title":"Cell Rep"},{"key":"8170_CR33","first-page":"594","volume":"26","author":"Z Nasrpour Navaei","year":"2023","unstructured":"Nasrpour Navaei Z, Taghehchian N, Zangouei AS, Abbaszadegan MR, Moghbeli M. MicroRNA-506 as a tumor suppressor in anaplastic thyroid carcinoma by regulation of WNT and NOTCH signaling pathways. Iran J Basic Med Sci. 2023;26:594\u2013602.","journal-title":"Iran J Basic Med Sci"},{"key":"8170_CR34","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1002\/path.2833","volume":"223","author":"MD Allen","year":"2011","unstructured":"Allen MD, Vaziri R, Green M, Chelala C, Brentnall AR, Dreger S, et al. Clinical and functional significance of \u03b19\u03b21 integrin expression in breast cancer: a novel cell-surface marker of the basal phenotype that promotes tumour cell invasion. J Pathol. 2011;223:646\u201358.","journal-title":"J Pathol"},{"key":"8170_CR35","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1038\/onc.2012.41","volume":"32","author":"SK Gupta","year":"2013","unstructured":"Gupta SK, Oommen S, Aubry MC, Williams BP, Vlahakis NE. Integrin \u03b19\u03b21 promotes malignant tumor growth and metastasis by potentiating epithelial-mesenchymal transition. Oncogene. 2013;32:141\u201350.","journal-title":"Oncogene"},{"key":"8170_CR36","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1001\/jamasurg.2013.5137","volume":"149","author":"MN Mavros","year":"2014","unstructured":"Mavros MN, Economopoulos KP, Alexiou VG, Pawlik TM. Treatment and prognosis for patients with intrahepatic cholangiocarcinoma: systematic review and meta-analysis. JAMA Surg. 2014;149:565\u201374.","journal-title":"JAMA Surg"},{"key":"8170_CR37","doi-asserted-by":"crossref","unstructured":"Chen L, Yin G, Wang Z, Liu Z, Sui C, Chen K, et al. A predictive radiotranscriptomics model based on DCE-MRI for tumor immune landscape and immunotherapy in cholangiocarcinoma. Biosci Trends. 2024;18:263\u201376.","DOI":"10.5582\/bst.2024.01121"},{"key":"8170_CR38","doi-asserted-by":"crossref","unstructured":"Yang J, Deng Q, Chen Z, Chen Y, Fu Z. BVES-AS1 suppresses the colorectal cancer progression via the miR-1269a\/b-SVEP1-PI3K\/AKT axis. Adv Clin Exp Med. 2024;33:1217\u201336","DOI":"10.17219\/acem\/175050"},{"key":"8170_CR39","doi-asserted-by":"publisher","first-page":"2596","DOI":"10.3390\/cancers16142596","volume":"16","author":"L Alaimo","year":"2024","unstructured":"Alaimo L, Boggio S, Catalano G, Calderone G, Poletto E, De Bellis M, et al. Multi-omics classification of intrahepatic cholangiocarcinoma: a systematic review and meta-analysis. Cancers. 2024;16:2596.","journal-title":"Cancers"},{"key":"8170_CR40","doi-asserted-by":"publisher","first-page":"837","DOI":"10.1158\/2159-8290.CD-19-0015","volume":"9","author":"S Yuan","year":"2019","unstructured":"Yuan S, Norgard RJ, Stanger BZ. Cellular plasticity in cancer. Cancer Discov. 2019;9:837\u201351.","journal-title":"Cancer Discov"},{"key":"8170_CR41","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1038\/s41576-020-00299-4","volume":"22","author":"E Persi","year":"2021","unstructured":"Persi E, Wolf YI, Horn D, Ruppin E, Demichelis F, Gatenby RA, et al. Mutation-selection balance and compensatory mechanisms in tumour evolution. Nat Rev Genet. 2021;22:251\u201362.","journal-title":"Nat Rev Genet"},{"key":"8170_CR42","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1038\/s41586-019-1730-1","volume":"575","author":"N Vasan","year":"2019","unstructured":"Vasan N, Baselga J, Hyman DM. A view on drug resistance in cancer. Nature. 2019;575:299\u2013309.","journal-title":"Nature"},{"key":"8170_CR43","doi-asserted-by":"publisher","first-page":"e61461","DOI":"10.7554\/eLife.61461","volume":"10","author":"A Sacchetti","year":"2021","unstructured":"Sacchetti A, Teeuwssen M, Verhagen M, Joosten R, Xu T, Stabile R, et al. Phenotypic plasticity underlies local invasion and distant metastasis in colon cancer. Elife. 2021;10:e61461.","journal-title":"Elife"},{"key":"8170_CR44","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1159\/000525976","volume":"14","author":"R Szalai","year":"2023","unstructured":"Szalai R, Till A, Szabo A, Melegh B, Hadzsiev K, Czako M. Overlapping interstitial deletions of the region 9q22.33 to 9q33.3 of three patients allow pinpointing candidate genes for epilepsy and cleft lip and palate. Mol Syndromol. 2023;14:109\u201322.","journal-title":"Mol Syndromol"},{"key":"8170_CR45","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2023.119479","volume":"1870","author":"SL Andrews","year":"2023","unstructured":"Andrews SL, Ghaderi-Najafabadi M, Gong P, Shamkhi N, Carleton L, Schofield C, et al. SVEP1 influences monocyte to macrophage differentiation via integrin \u03b14\u03b21\/\u03b19\u03b21 and Rho\/Rac signalling. Biochim Biophys Acta Mol Cell Res. 2023;1870:119479.","journal-title":"Biochim Biophys Acta Mol Cell Res"},{"key":"8170_CR46","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1038\/s41556-018-0223-z","volume":"21","author":"P Moreno-Layseca","year":"2019","unstructured":"Moreno-Layseca P, Icha J, Hamidi H, Ivaska J. Integrin trafficking in cells and tissues. Nat Cell Biol. 2019;21:122\u201332.","journal-title":"Nat Cell Biol"},{"key":"8170_CR47","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1038\/nrm1490","volume":"5","author":"W Guo","year":"2004","unstructured":"Guo W, Giancotti FG. Integrin signalling during tumour progression. Nat Rev Mol Cell Biol. 2004;5:816\u201326.","journal-title":"Nat Rev Mol Cell Biol"},{"key":"8170_CR48","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-019-0991-5","volume":"18","author":"L Mashouri","year":"2019","unstructured":"Mashouri L, Yousefi H, Aref AR, Ahadi AM, Molaei F, Alahari SK. Exosomes: composition, biogenesis, and mechanisms in cancer metastasis and drug resistance. Mol Cancer. 2019;18:75.","journal-title":"Mol Cancer"},{"key":"8170_CR49","doi-asserted-by":"publisher","first-page":"2726","DOI":"10.1016\/j.apsb.2021.01.004","volume":"11","author":"M Li","year":"2021","unstructured":"Li M, Wang Y, Li M, Wu X, Setrerrahmane S, Xu H. Integrins as attractive targets for cancer therapeutics. Acta Pharm Sin B. 2021;11:2726\u201337.","journal-title":"Acta Pharm Sin B"},{"key":"8170_CR50","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1186\/s13046-018-0694-6","volume":"37","author":"J Luo","year":"2018","unstructured":"Luo J, Yao JF, Deng XF, Zheng XD, Jia M, Wang YQ, et al. 14, 15-EET induces breast cancer cell EMT and cisplatin resistance by up-regulating integrin \u03b1v\u03b23 and activating FAK\/PI3K\/AKT signaling. J Exp Clin Cancer Res. 2018;37:23.","journal-title":"J Exp Clin Cancer Res"},{"key":"8170_CR51","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1186\/s12929-022-00824-z","volume":"29","author":"TH Jang","year":"2022","unstructured":"Jang TH, Huang WC, Tung SL, Lin SC, Chen PM, Cho CY, et al. MicroRNA-485-5p targets keratin 17 to regulate oral cancer stemness and chemoresistance via the integrin\/FAK\/Src\/ERK\/\u03b2-catenin pathway. J Biomed Sci. 2022;29:42.","journal-title":"J Biomed Sci"},{"key":"8170_CR52","doi-asserted-by":"publisher","first-page":"4431","DOI":"10.7150\/thno.71364","volume":"12","author":"JI Choi","year":"2022","unstructured":"Choi JI, Rim JH, Jang SI, Park JS, Park H, Cho JH, et al. The role of Jagged1 as a dynamic switch of cancer cell plasticity in PDAC assembloids. Theranostics. 2022;12:4431\u201345.","journal-title":"Theranostics"},{"key":"8170_CR53","doi-asserted-by":"publisher","first-page":"4566","DOI":"10.1158\/1078-0432.CCR-17-1952","volume":"24","author":"D Shah","year":"2018","unstructured":"Shah D, Wyatt D, Baker AT, Simms P, Peiffer DS, Fernandez M, et al. Inhibition of HER2 increases JAGGED1-dependent breast cancer stem cells: role for membrane JAGGED1. Clin Cancer Res. 2018;24:4566\u201378.","journal-title":"Clin Cancer Res"},{"key":"8170_CR54","doi-asserted-by":"publisher","first-page":"2275","DOI":"10.1111\/liv.15691","volume":"43","author":"A Yoshizumi","year":"2023","unstructured":"Yoshizumi A, Kuboki S, Takayashiki T, Takano S, Takayanagi R, Sonoda I, et al. Tspan15-ADAM10 signalling enhances cancer stem cell-like properties and induces chemoresistance via Notch1 activation in ICC. Liver Int. 2023;43:2275\u201391.","journal-title":"Liver Int"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-08170-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-08170-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-08170-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T16:02:35Z","timestamp":1764345755000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-08170-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,28]]},"references-count":54,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["8170"],"URL":"https:\/\/doi.org\/10.1038\/s41419-025-08170-2","relation":{},"ISSN":["2041-4889"],"issn-type":[{"type":"electronic","value":"2041-4889"}],"subject":[],"published":{"date-parts":[[2025,11,28]]},"assertion":[{"value":"13 April 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 September 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 October 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 November 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"Informed consent was obtained from all participants involved in this study. Approval for this clinical research was granted by the Medical Ethics Committee of Tianjin Medical University Cancer Institute and Hospital (Approval number: Ek2023045). And the study-related animal experiments were approved by the Experimental Animal Ethics Committee (Approval number: NSFC-AE-2023037) of Tianjin Medical University Cancer Institute and Hospital, and the study was conducted in compliance with the Declaration of Helsinki.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}],"article-number":"871"}}