{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T13:05:43Z","timestamp":1783947943810,"version":"3.55.0"},"reference-count":44,"publisher":"Wiley","issue":"32","license":[{"start":{"date-parts":[[2023,9,25]],"date-time":"2023-09-25T00:00:00Z","timestamp":1695600000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"publisher","award":["PID2019\u2010104734RB\u2010I00"],"award-info":[{"award-number":["PID2019\u2010104734RB\u2010I00"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2023,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Phosphatase and TENsin homolog (Pten) and p53 are two of the most frequently mutated tumor suppressor genes in endometrial cancer. However, the functional consequences and histopathological manifestation of concomitant p53 and Pten loss of function alterations in the development of endometrial cancer is still controversial. Here, it is demonstrated that simultaneous Pten and p53 deletion is sufficient to cause epithelial to mesenchymal transition phenotype in endometrial organoids. By a novel intravaginal delivery method using HIV1 trans\u2010activator of transcription cell penetrating peptide fused with a Cre recombinase protein (TAT\u2010Cre), local ablation of both p53 and Pten is achieved specifically in the uterus. These mice developed high\u2010grade endometrial carcinomas and a high percentage of uterine carcinosarcomas resembling those found in humans. To further demonstrate that carcinosarcomas arise from epithelium, double Pten\/p53 deficient epithelial cells are mixed with wild type stromal and myometrial cells and subcutaneously transplanted to Scid mice. All xenotransplants resulted in the development of uterine carcinosarcomas displaying high nuclear pleomorphism and metastatic potential. Accordingly, in vivo CRISPR\/Cas9 disruption of Pten and p53 also triggered the development of metastatic carcinosarcomas. The results unfadingly demonstrate that simultaneous deletion of p53 and Pten in endometrial epithelial cells is enough to trigger epithelial to mesenchymal transition that is consistently translated to the formation of uterine carcinosarcomas in vivo.<\/jats:p>","DOI":"10.1002\/advs.202303134","type":"journal-article","created":{"date-parts":[[2023,9,26]],"date-time":"2023-09-26T01:15:21Z","timestamp":1695690921000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["In Vivo Intra\u2010Uterine Delivery of TAT\u2010Fused Cre Recombinase and CRISPR\/Cas9 Editing System in Mice Unveil Histopathology of Pten\/p53\u2010Deficient Endometrial Cancers"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1622-5311","authenticated-orcid":false,"given":"Ra\u00fal","family":"Navaridas","sequence":"first","affiliation":[{"name":"Developmental and Oncogenic Signalling Group, Department of Basic Medical Sciences and Department of Experimental Medicine Institut de Recerca Biom\u00e8dica de Lleida, IRBLleida. University of Lleida, UdL.  Av. Rovira Roure 80 Lleida Catalonia 25198 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4154-6061","authenticated-orcid":false,"given":"Maria","family":"Vidal\u2010Saban\u00e9s","sequence":"additional","affiliation":[{"name":"Developmental and Oncogenic Signalling Group, Department of Basic Medical Sciences and Department of Experimental Medicine Institut de Recerca Biom\u00e8dica de Lleida, IRBLleida. University of Lleida, UdL.  Av. Rovira Roure 80 Lleida Catalonia 25198 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2364-1551","authenticated-orcid":false,"given":"Anna","family":"Ruiz\u2010Mitjana","sequence":"additional","affiliation":[{"name":"Developmental and Oncogenic Signalling Group, Department of Basic Medical Sciences and Department of Experimental Medicine Institut de Recerca Biom\u00e8dica de Lleida, IRBLleida. University of Lleida, UdL.  Av. Rovira Roure 80 Lleida Catalonia 25198 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6669-5410","authenticated-orcid":false,"given":"Gisela","family":"Alt\u00e9s","sequence":"additional","affiliation":[{"name":"Developmental and Oncogenic Signalling Group, Department of Basic Medical Sciences and Department of Experimental Medicine Institut de Recerca Biom\u00e8dica de Lleida, IRBLleida. University of Lleida, UdL.  Av. Rovira Roure 80 Lleida Catalonia 25198 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0781-3093","authenticated-orcid":false,"given":"Aida","family":"Perramon\u2010G\u00fcell","sequence":"additional","affiliation":[{"name":"Developmental and Oncogenic Signalling Group, Department of Basic Medical Sciences and Department of Experimental Medicine Institut de Recerca Biom\u00e8dica de Lleida, IRBLleida. University of Lleida, UdL.  Av. Rovira Roure 80 Lleida Catalonia 25198 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9569-6316","authenticated-orcid":false,"given":"Andree","family":"Yeramian","sequence":"additional","affiliation":[{"name":"Developmental and Oncogenic Signalling Group, Department of Basic Medical Sciences and Department of Experimental Medicine Institut de Recerca Biom\u00e8dica de Lleida, IRBLleida. University of Lleida, UdL.  Av. Rovira Roure 80 Lleida Catalonia 25198 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1164-8377","authenticated-orcid":false,"given":"Joaquim","family":"Egea","sequence":"additional","affiliation":[{"name":"Developmental and Oncogenic Signalling Group, Department of Basic Medical Sciences and Department of Experimental Medicine Institut de Recerca Biom\u00e8dica de Lleida, IRBLleida. University of Lleida, UdL.  Av. Rovira Roure 80 Lleida Catalonia 25198 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3509-7431","authenticated-orcid":false,"given":"Mario","family":"Encinas","sequence":"additional","affiliation":[{"name":"Developmental and Oncogenic Signalling Group, Department of Basic Medical Sciences and Department of Experimental Medicine Institut de Recerca Biom\u00e8dica de Lleida, IRBLleida. University of Lleida, UdL.  Av. Rovira Roure 80 Lleida Catalonia 25198 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1636-6010","authenticated-orcid":false,"given":"Sonia","family":"Gatius","sequence":"additional","affiliation":[{"name":"Oncologic Pathology Group, Department of Basic Medical Sciences Biomedical Research Institute of Lleida (IRBLleida), CIBERONC.  Av. Rovira Roure 80 Lleida Catalonia 25198 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7201-6605","authenticated-orcid":false,"given":"Xavier","family":"Matias\u2010Guiu","sequence":"additional","affiliation":[{"name":"Oncologic Pathology Group, Department of Basic Medical Sciences Biomedical Research Institute of Lleida (IRBLleida), CIBERONC.  Av. Rovira Roure 80 Lleida Catalonia 25198 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1921-0449","authenticated-orcid":false,"given":"Xavier","family":"Dolcet","sequence":"additional","affiliation":[{"name":"Developmental and Oncogenic Signalling Group, Department of Basic Medical Sciences and Department of Experimental Medicine Institut de Recerca Biom\u00e8dica de Lleida, IRBLleida. University of Lleida, UdL.  Av. Rovira Roure 80 Lleida Catalonia 25198 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,9,25]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-021-00324-8"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)00323-3"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-020117-043609"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/0090-8258(83)90111-7"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1136\/ijgc-2022-004073"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature12113"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers11070964"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/IGC.0b013e3181c83675"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.2009.5"},{"key":"e_1_2_9_10_1","first-page":"4575","volume":"17","author":"Stavropoulos A.","year":"2019","journal-title":"Oncol. Lett."},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2021.798628"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19082348"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1097-143"},{"key":"e_1_2_9_14_1","first-page":"4736","volume":"57","author":"Risinger J. I.","year":"1997","journal-title":"Cancer Res."},{"key":"e_1_2_9_15_1","first-page":"3935","volume":"57","author":"Tashiro H.","year":"1997","journal-title":"Cancer Res."},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/1235"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.4.1563"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(07)00488-5"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/emmm.201101063"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-1274"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/cac2.12409"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.011445"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2010.090974"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2017.73"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/dvg.20335"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/dc.21426"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0134969"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-21-1059"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1007630"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1009986"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2014.193"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2012.232"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.047035"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/gene.20098"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1210\/me.2003-0404"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.004440"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1911310116"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2014-1265"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-16416-0"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygyno.2004.06.008"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2011.03.006"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13194990"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-019-0032-3"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btw561"}],"container-title":["Advanced Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.202303134","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T16:09:41Z","timestamp":1759766981000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/advs.202303134"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,25]]},"references-count":44,"journal-issue":{"issue":"32","published-print":{"date-parts":[[2023,11]]}},"alternative-id":["10.1002\/advs.202303134"],"URL":"https:\/\/doi.org\/10.1002\/advs.202303134","archive":["Portico"],"relation":{},"ISSN":["2198-3844","2198-3844"],"issn-type":[{"value":"2198-3844","type":"print"},{"value":"2198-3844","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,25]]},"assertion":[{"value":"2023-05-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-09-25","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"2303134"}}