{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T16:35:00Z","timestamp":1790440500977,"version":"4.1.0"},"reference-count":46,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2021,6,27]],"date-time":"2021-06-27T00:00:00Z","timestamp":1624752000000},"content-version":"vor","delay-in-days":26,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007219","name":"Natural Science Foundation of Shanghai","doi-asserted-by":"publisher","award":["20ZR143410"],"award-info":[{"award-number":["20ZR143410"]}],"id":[{"id":"10.13039\/100007219","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009018","name":"Shanghai Municipal Human Resources and Social Security Bureau","doi-asserted-by":"publisher","award":["2018060"],"award-info":[{"award-number":["2018060"]}],"id":[{"id":"10.13039\/501100009018","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp; Translational Med"],"published-print":{"date-parts":[[2021,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Gallbladder cancer (GC) is a malignant disease characterized with highly cellular heterogeneity and poor prognosis. Determining the intratumoral heterogeneity and microenvironment (TME) can provide novel therapeutic strategies for GC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We performed the single\u2010cell RNA sequencing on the primary and lymph node metastatic gallbladder tumors and the adjacent normal tissues of five patients. The transcriptomic atlas and ligand\u2013receptor\u2010based intercellular communication networks of the single cells were characterized.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The transcriptomic landscape of 24,887 single cells was obtained and characterized as 10 cellular clusters, including epithelial, neuroendocrine tumor cells, T&amp;NK cells, B cells, RGS5+ fibroblasts, POSTN+ fibroblasts, PDGFRA+ fibroblasts, endothelial, myeloid cells, and mast cells. Different types of GC harbored distinct epithelial tumor subpopulations, and squamous cell carcinoma could be differentiated from adenocarcinoma cells. Abundant immune cells infiltrated into adenocarcinoma and squamous cell carcinoma, rather than neuroendocrine neoplasms, which showed significant enrichment of stromal cells. CD4+\/FOXP3+ T\u2010reg and CD4+\/CXCL13+ T helper cells with higher exhausting biomarkers, as well as a dynamic lineage transition of tumor\u2010associated macrophages from CCL20<jats:sup>hi<\/jats:sup>\/CD163<jats:sup>lo<\/jats:sup>, CCL20<jats:sup>lo<\/jats:sup>\/CD163<jats:sup>hi<\/jats:sup> to APOE+, were identified in GC tissues, suggesting the immunosuppressive and tumor\u2010promoting status of immune cells in TME. Two distinct endothelial cells (KDR+ and ACKR1+), which were involved in angiogenesis and lymphangiogenesis, showed remarkable ligand\u2013receptor interactions with primary GC cells and macrophages in gallbladder tumors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This study reveals a widespread reprogramming across multiple cell populations in GC progression, dissects the cellular heterogeneity and interactions in gallbladder TME, and provides potential therapeutic targets for GC.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.462","type":"journal-article","created":{"date-parts":[[2021,6,27]],"date-time":"2021-06-27T09:36:10Z","timestamp":1624786570000},"source":"Crossref","is-referenced-by-count":59,"title":["Diversity and intratumoral heterogeneity in human gallbladder cancer progression revealed by single\u2010cell RNA sequencing"],"prefix":"10.1002","volume":"11","author":[{"given":"Peizhan","family":"Chen","sequence":"first","affiliation":[{"name":"State Key Laboratory of Oncogenes and Related Genes Center for Single\u2010Cell Omics School of Public Health Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueqi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of General Surgery Zhongshan Hospital Fudan University  Shanghai China"},{"name":"Biliary Tract Diseases Institute Fudan University  Shanghai China"},{"name":"Cancer Center Zhongshan Hospital Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingquan","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncogenes and Related Genes Center for Single\u2010Cell Omics School of Public Health Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaobo","family":"Bo","sequence":"additional","affiliation":[{"name":"Department of General Surgery Zhongshan Hospital Fudan University  Shanghai China"},{"name":"Biliary Tract Diseases Institute Fudan University  Shanghai China"},{"name":"Cancer Center Zhongshan Hospital Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of General Surgery Zhongshan Hospital Fudan University  Shanghai China"},{"name":"Biliary Tract Diseases Institute Fudan University  Shanghai China"},{"name":"Cancer Center Zhongshan Hospital Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingxi","family":"Nan","sequence":"additional","affiliation":[{"name":"Department of General Surgery Zhongshan Hospital Fudan University  Shanghai China"},{"name":"Biliary Tract Diseases Institute Fudan University  Shanghai China"},{"name":"Cancer Center Zhongshan Hospital Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changcheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of General Surgery Zhongshan Hospital Fudan University  Shanghai China"},{"name":"Biliary Tract Diseases Institute Fudan University  Shanghai China"},{"name":"Cancer Center Zhongshan Hospital Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Ba","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncogenes and Related Genes Center for Single\u2010Cell Omics School of Public Health Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Houbao","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of General Surgery Zhongshan Hospital Fudan University  Shanghai China"},{"name":"Biliary Tract Diseases Institute Fudan University  Shanghai China"},{"name":"Cancer Center Zhongshan Hospital Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2791-8981","authenticated-orcid":false,"given":"Hui","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncogenes and Related Genes Center for Single\u2010Cell Omics School of Public Health Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,6,27]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.2679"},{"key":"e_1_2_10_3_1","first-page":"99","article-title":"Gallbladder cancer: epidemiology and outcome","volume":"6","author":"Hundal R","year":"2014","journal-title":"Clin Epidemiol"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2016.04.047"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13277-014-2200-x"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2018-316039"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3030"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/cas.14078"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/cas.14239"},{"issue":"1","key":"e_1_2_10_10_1","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1186\/s12885-018-4651-8","article-title":"Classification of gallbladder cancer by assessment of CD8(+) TIL and PD\u2010L1 expression","volume":"18","author":"Lin J","year":"2018","journal-title":"BMC Cancer"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1136\/lupus-2019-000329"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-20019-0"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-16164-1"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1245\/s10434-019-07440-6"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-19-0286"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1303932110"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa407"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1922-8"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.4161\/onci.22354"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2006.06.011"},{"issue":"17","key":"e_1_2_10_21_1","first-page":"4884","article-title":"Granzyme B\u2010mediated degradation of T\u2010cell receptor zeta chain","volume":"62","author":"Wieckowski E","year":"2002","journal-title":"Cancer Res"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2020.100993"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/16.21.6355"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.11.045"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.03059"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-18916-5"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-005-5426-3"},{"issue":"1","key":"e_1_2_10_28_1","doi-asserted-by":"crossref","first-page":"86","DOI":"10.2174\/156652409787314480","article-title":"Atypical chemokine receptors in inflammatory disease","volume":"9","author":"Patel M","year":"2009","journal-title":"Curr Mol Med"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1631-3"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-020-0292-x"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2017.7719"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.12998\/wjcc.v7.i23.4163"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-018-0479-7"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-5320(68)80098-X"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00147"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pt.2012.01.004"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4380"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4096"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-019-0619-0"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2019.11.014"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-020-0355-0"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15081"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1254257"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4402"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-13420-x"},{"issue":"1","key":"e_1_2_10_47_1","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1093\/nar\/gkv806","article-title":"ROTS: reproducible RNA\u2010seq biomarker detector\u2010prognostic markers for clear cell renal cell cancer","volume":"44","author":"Seyednasrollah F","year":"2016","journal-title":"Nucleic Acids Res"}],"container-title":["Clinical and Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ctm2.462","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ctm2.462","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ctm2.462","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,29]],"date-time":"2023-08-29T19:09:23Z","timestamp":1693336163000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ctm2.462"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6]]},"references-count":46,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2021,6]]}},"alternative-id":["10.1002\/ctm2.462"],"URL":"https:\/\/doi.org\/10.1002\/ctm2.462","archive":["Portico"],"relation":{},"ISSN":["2001-1326","2001-1326"],"issn-type":[{"value":"2001-1326","type":"print"},{"value":"2001-1326","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6]]},"article-number":"e462"}}