Inhibition of lung tumorigenesis by transient reprogramming in cancer cells
Abstract Oncogenic transformation and Oct4, Sox2, Klf4 and c-Myc (OSKM)-mediated induction of pluripotency are two independent and incompatible cellular fates. While continuous expression of OSKM can convert normal somatic cells into teratogenic pluripotent cells, it remains speculative what is the...
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| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2024-11-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-024-07207-2 |
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| author | Pablo Pedrosa Zhenguang Zhang Victor Nuñez-Quintela David Macias Jianfeng Ge Mary Denholm Anna Dyas Valentin Estevez-Souto Patricia Lado-Fernandez Patricia Gonzalez Maria Gomez Jose Ezequiel Martin Sabela Da Silva-Alvarez Manuel Collado Daniel Muñoz-Espín |
| author_facet | Pablo Pedrosa Zhenguang Zhang Victor Nuñez-Quintela David Macias Jianfeng Ge Mary Denholm Anna Dyas Valentin Estevez-Souto Patricia Lado-Fernandez Patricia Gonzalez Maria Gomez Jose Ezequiel Martin Sabela Da Silva-Alvarez Manuel Collado Daniel Muñoz-Espín |
| author_sort | Pablo Pedrosa |
| collection | DOAJ |
| description | Abstract Oncogenic transformation and Oct4, Sox2, Klf4 and c-Myc (OSKM)-mediated induction of pluripotency are two independent and incompatible cellular fates. While continuous expression of OSKM can convert normal somatic cells into teratogenic pluripotent cells, it remains speculative what is the impact of transient OSKM expression in cancer cells. Here, we find that OSKM expression limits the growth of transformed lung cells by inducing apoptosis and senescence. We identify Oct4 and Klf4 as the main individual reprogramming factors responsible for this effect. Mechanistically, the induction of cell cycle inhibitor p21 downstream of the reprogramming factors acts as mediator of cell death and senescence. Using a variety of in vivo systems, including allografts, orthotopic transplantation and KRAS-driven lung cancer mouse models, we demonstrate that transient reprogramming by OSKM expression in cancer cells impairs tumor growth and reduces tumor burden. Altogether, our results show that the induction of transient reprogramming in cancer cells is antitumorigenic opening novel potential therapeutic avenues in oncology. |
| format | Article |
| id | doaj-art-37a764e4504b4b1a8c8266ffd91ece4d |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-37a764e4504b4b1a8c8266ffd91ece4d2024-12-01T12:47:24ZengNature Publishing GroupCell Death and Disease2041-48892024-11-01151111610.1038/s41419-024-07207-2Inhibition of lung tumorigenesis by transient reprogramming in cancer cellsPablo Pedrosa0Zhenguang Zhang1Victor Nuñez-Quintela2David Macias3Jianfeng Ge4Mary Denholm5Anna Dyas6Valentin Estevez-Souto7Patricia Lado-Fernandez8Patricia Gonzalez9Maria Gomez10Jose Ezequiel Martin11Sabela Da Silva-Alvarez12Manuel Collado13Daniel Muñoz-Espín14Cell Senescence, Cancer and Aging Laboratory, Health Research Institute of Santiago de Compostela (IDIS)Early Cancer Institute, Department of Oncology, University of CambridgeEarly Cancer Institute, Department of Oncology, University of CambridgeEarly Cancer Institute, Department of Oncology, University of CambridgeEarly Cancer Institute, Department of Oncology, University of CambridgeEarly Cancer Institute, Department of Oncology, University of CambridgeEarly Cancer Institute, Department of Oncology, University of CambridgeCell Senescence, Cancer and Aging Laboratory, Health Research Institute of Santiago de Compostela (IDIS)Cell Senescence, Cancer and Aging Laboratory, Health Research Institute of Santiago de Compostela (IDIS)Histopathology Unit, Spanish National Cancer Research Centre (CNIO)Histopathology Unit, Spanish National Cancer Research Centre (CNIO)CMDL, Department of Oncology, SMCL, Department of Medical Genetics, University of CambridgeCell Senescence, Cancer and Aging Laboratory, Health Research Institute of Santiago de Compostela (IDIS)Cell Senescence, Cancer and Aging Laboratory, Health Research Institute of Santiago de Compostela (IDIS)Early Cancer Institute, Department of Oncology, University of CambridgeAbstract Oncogenic transformation and Oct4, Sox2, Klf4 and c-Myc (OSKM)-mediated induction of pluripotency are two independent and incompatible cellular fates. While continuous expression of OSKM can convert normal somatic cells into teratogenic pluripotent cells, it remains speculative what is the impact of transient OSKM expression in cancer cells. Here, we find that OSKM expression limits the growth of transformed lung cells by inducing apoptosis and senescence. We identify Oct4 and Klf4 as the main individual reprogramming factors responsible for this effect. Mechanistically, the induction of cell cycle inhibitor p21 downstream of the reprogramming factors acts as mediator of cell death and senescence. Using a variety of in vivo systems, including allografts, orthotopic transplantation and KRAS-driven lung cancer mouse models, we demonstrate that transient reprogramming by OSKM expression in cancer cells impairs tumor growth and reduces tumor burden. Altogether, our results show that the induction of transient reprogramming in cancer cells is antitumorigenic opening novel potential therapeutic avenues in oncology.https://doi.org/10.1038/s41419-024-07207-2 |
| spellingShingle | Pablo Pedrosa Zhenguang Zhang Victor Nuñez-Quintela David Macias Jianfeng Ge Mary Denholm Anna Dyas Valentin Estevez-Souto Patricia Lado-Fernandez Patricia Gonzalez Maria Gomez Jose Ezequiel Martin Sabela Da Silva-Alvarez Manuel Collado Daniel Muñoz-Espín Inhibition of lung tumorigenesis by transient reprogramming in cancer cells Cell Death and Disease |
| title | Inhibition of lung tumorigenesis by transient reprogramming in cancer cells |
| title_full | Inhibition of lung tumorigenesis by transient reprogramming in cancer cells |
| title_fullStr | Inhibition of lung tumorigenesis by transient reprogramming in cancer cells |
| title_full_unstemmed | Inhibition of lung tumorigenesis by transient reprogramming in cancer cells |
| title_short | Inhibition of lung tumorigenesis by transient reprogramming in cancer cells |
| title_sort | inhibition of lung tumorigenesis by transient reprogramming in cancer cells |
| url | https://doi.org/10.1038/s41419-024-07207-2 |
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