In Vivo Intra‐Uterine Delivery of TAT‐Fused Cre Recombinase and CRISPR/Cas9 Editing System in Mice Unveil Histopathology of Pten/p53‐Deficient Endometrial Cancers
Abstract 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 endometr...
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| Format: | Article |
| Language: | English |
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Wiley
2023-11-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202303134 |
| _version_ | 1797627753800925184 |
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| author | Raúl Navaridas Maria Vidal‐Sabanés Anna Ruiz‐Mitjana Gisela Altés Aida Perramon‐Güell Andree Yeramian Joaquim Egea Mario Encinas Sonia Gatius Xavier Matias‐Guiu Xavier Dolcet |
| author_facet | Raúl Navaridas Maria Vidal‐Sabanés Anna Ruiz‐Mitjana Gisela Altés Aida Perramon‐Güell Andree Yeramian Joaquim Egea Mario Encinas Sonia Gatius Xavier Matias‐Guiu Xavier Dolcet |
| author_sort | Raúl Navaridas |
| collection | DOAJ |
| description | Abstract 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‐activator of transcription cell penetrating peptide fused with a Cre recombinase protein (TAT‐Cre), local ablation of both p53 and Pten is achieved specifically in the uterus. These mice developed high‐grade 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. |
| first_indexed | 2024-03-11T10:28:49Z |
| format | Article |
| id | doaj.art-a10e9bdc8afb41bba8c8fa70ed603e4f |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-03-11T10:28:49Z |
| publishDate | 2023-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-a10e9bdc8afb41bba8c8fa70ed603e4f2023-11-15T05:46:35ZengWileyAdvanced Science2198-38442023-11-011032n/an/a10.1002/advs.202303134In Vivo Intra‐Uterine Delivery of TAT‐Fused Cre Recombinase and CRISPR/Cas9 Editing System in Mice Unveil Histopathology of Pten/p53‐Deficient Endometrial CancersRaúl Navaridas0Maria Vidal‐Sabanés1Anna Ruiz‐Mitjana2Gisela Altés3Aida Perramon‐Güell4Andree Yeramian5Joaquim Egea6Mario Encinas7Sonia Gatius8Xavier Matias‐Guiu9Xavier Dolcet10Developmental and Oncogenic Signalling Group, Department of Basic Medical Sciences and Department of Experimental Medicine Institut de Recerca Biomèdica de Lleida, IRBLleida. University of Lleida, UdL. Av. Rovira Roure 80 Lleida Catalonia 25198 SpainDevelopmental and Oncogenic Signalling Group, Department of Basic Medical Sciences and Department of Experimental Medicine Institut de Recerca Biomèdica de Lleida, IRBLleida. University of Lleida, UdL. Av. Rovira Roure 80 Lleida Catalonia 25198 SpainDevelopmental and Oncogenic Signalling Group, Department of Basic Medical Sciences and Department of Experimental Medicine Institut de Recerca Biomèdica de Lleida, IRBLleida. University of Lleida, UdL. Av. Rovira Roure 80 Lleida Catalonia 25198 SpainDevelopmental and Oncogenic Signalling Group, Department of Basic Medical Sciences and Department of Experimental Medicine Institut de Recerca Biomèdica de Lleida, IRBLleida. University of Lleida, UdL. Av. Rovira Roure 80 Lleida Catalonia 25198 SpainDevelopmental and Oncogenic Signalling Group, Department of Basic Medical Sciences and Department of Experimental Medicine Institut de Recerca Biomèdica de Lleida, IRBLleida. University of Lleida, UdL. Av. Rovira Roure 80 Lleida Catalonia 25198 SpainDevelopmental and Oncogenic Signalling Group, Department of Basic Medical Sciences and Department of Experimental Medicine Institut de Recerca Biomèdica de Lleida, IRBLleida. University of Lleida, UdL. Av. Rovira Roure 80 Lleida Catalonia 25198 SpainDevelopmental and Oncogenic Signalling Group, Department of Basic Medical Sciences and Department of Experimental Medicine Institut de Recerca Biomèdica de Lleida, IRBLleida. University of Lleida, UdL. Av. Rovira Roure 80 Lleida Catalonia 25198 SpainDevelopmental and Oncogenic Signalling Group, Department of Basic Medical Sciences and Department of Experimental Medicine Institut de Recerca Biomèdica de Lleida, IRBLleida. University of Lleida, UdL. Av. Rovira Roure 80 Lleida Catalonia 25198 SpainOncologic Pathology Group, Department of Basic Medical Sciences Biomedical Research Institute of Lleida (IRBLleida), CIBERONC. Av. Rovira Roure 80 Lleida Catalonia 25198 SpainOncologic Pathology Group, Department of Basic Medical Sciences Biomedical Research Institute of Lleida (IRBLleida), CIBERONC. Av. Rovira Roure 80 Lleida Catalonia 25198 SpainDevelopmental and Oncogenic Signalling Group, Department of Basic Medical Sciences and Department of Experimental Medicine Institut de Recerca Biomèdica de Lleida, IRBLleida. University of Lleida, UdL. Av. Rovira Roure 80 Lleida Catalonia 25198 SpainAbstract 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‐activator of transcription cell penetrating peptide fused with a Cre recombinase protein (TAT‐Cre), local ablation of both p53 and Pten is achieved specifically in the uterus. These mice developed high‐grade 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.https://doi.org/10.1002/advs.202303134cell penetrating peptidesCre‐recombinaseCRISPR/Cas9endometrial cancerHIV1‐TATmouse model of cancer |
| spellingShingle | Raúl Navaridas Maria Vidal‐Sabanés Anna Ruiz‐Mitjana Gisela Altés Aida Perramon‐Güell Andree Yeramian Joaquim Egea Mario Encinas Sonia Gatius Xavier Matias‐Guiu Xavier Dolcet In Vivo Intra‐Uterine Delivery of TAT‐Fused Cre Recombinase and CRISPR/Cas9 Editing System in Mice Unveil Histopathology of Pten/p53‐Deficient Endometrial Cancers Advanced Science cell penetrating peptides Cre‐recombinase CRISPR/Cas9 endometrial cancer HIV1‐TAT mouse model of cancer |
| title | In Vivo Intra‐Uterine Delivery of TAT‐Fused Cre Recombinase and CRISPR/Cas9 Editing System in Mice Unveil Histopathology of Pten/p53‐Deficient Endometrial Cancers |
| title_full | In Vivo Intra‐Uterine Delivery of TAT‐Fused Cre Recombinase and CRISPR/Cas9 Editing System in Mice Unveil Histopathology of Pten/p53‐Deficient Endometrial Cancers |
| title_fullStr | In Vivo Intra‐Uterine Delivery of TAT‐Fused Cre Recombinase and CRISPR/Cas9 Editing System in Mice Unveil Histopathology of Pten/p53‐Deficient Endometrial Cancers |
| title_full_unstemmed | In Vivo Intra‐Uterine Delivery of TAT‐Fused Cre Recombinase and CRISPR/Cas9 Editing System in Mice Unveil Histopathology of Pten/p53‐Deficient Endometrial Cancers |
| title_short | In Vivo Intra‐Uterine Delivery of TAT‐Fused Cre Recombinase and CRISPR/Cas9 Editing System in Mice Unveil Histopathology of Pten/p53‐Deficient Endometrial Cancers |
| title_sort | in vivo intra uterine delivery of tat fused cre recombinase and crispr cas9 editing system in mice unveil histopathology of pten p53 deficient endometrial cancers |
| topic | cell penetrating peptides Cre‐recombinase CRISPR/Cas9 endometrial cancer HIV1‐TAT mouse model of cancer |
| url | https://doi.org/10.1002/advs.202303134 |
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