p53-loss induced prostatic epithelial cell plasticity and invasion is driven by a crosstalk with the tumor microenvironment
Abstract Prostate cancer is a heterogeneous disease with a slow progression and a highly variable clinical outcome. The tumor suppressor genes PTEN and TP53 are frequently mutated in prostate cancer and are predictive of early metastatic dissemination and unfavorable patient outcomes. The progressio...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-01-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07361-1 |
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| author | Darya Yanushko Beatriz German Falcon Rana El Bizri Despoina Pervizou Robin Dolgos Céline Keime Tao Ye Christelle Thibault-Carpentier Clementine Le Magnen Sandrine Henri Gilles Laverny Daniel Metzger |
| author_facet | Darya Yanushko Beatriz German Falcon Rana El Bizri Despoina Pervizou Robin Dolgos Céline Keime Tao Ye Christelle Thibault-Carpentier Clementine Le Magnen Sandrine Henri Gilles Laverny Daniel Metzger |
| author_sort | Darya Yanushko |
| collection | DOAJ |
| description | Abstract Prostate cancer is a heterogeneous disease with a slow progression and a highly variable clinical outcome. The tumor suppressor genes PTEN and TP53 are frequently mutated in prostate cancer and are predictive of early metastatic dissemination and unfavorable patient outcomes. The progression of solid tumors to metastasis is often associated with increased cell plasticity, but the complex events underlying TP53-loss-induced disease aggressiveness remain incompletely understood. Using genetically engineered mice, we show that Trp53 deficiency in Pten-null prostatic epithelial cells (PECs) does not impact early cell proliferation and neoplasia formation, nor growth arrest and senescence entry at a later time. However, Trp53-deficiency enhances invasive adenocarcinoma development and promotes metastatic cell dissemination. Importantly, our single-cell transcriptomic and chromatin accessibility analyses combined with histological examinations uncovered an epithelial cell population characterized by an induction of Jak/Stat3 signaling and displaying mesenchymal features. Moreover, we show that the transcriptomic signature of this cell population is prominent in tumors of patients with high-risk prostate cancer or metastatic disease. In addition, our in vivo and organoid-based experiments provide evidence that PEC plasticity occurs through bi-directional communication with cancer-associated fibroblasts (CAFs). Thus, our study demonstrates that p53 loss induces a protumorigenic crosstalk between PECs and CAFs, and identifies new vulnerabilities that might be targeted to limit cancer progression. |
| format | Article |
| id | doaj-art-89a56349e5044d71bc9731d416fbfbd7 |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-89a56349e5044d71bc9731d416fbfbd72025-01-26T12:54:41ZengNature Publishing GroupCell Death and Disease2041-48892025-01-0116111210.1038/s41419-025-07361-1p53-loss induced prostatic epithelial cell plasticity and invasion is driven by a crosstalk with the tumor microenvironmentDarya Yanushko0Beatriz German Falcon1Rana El Bizri2Despoina Pervizou3Robin Dolgos4Céline Keime5Tao Ye6Christelle Thibault-Carpentier7Clementine Le Magnen8Sandrine Henri9Gilles Laverny10Daniel Metzger11Institut de Génétique et de Biologie Moléculaire et CellulaireInstitut de Génétique et de Biologie Moléculaire et CellulaireInstitut de Génétique et de Biologie Moléculaire et CellulaireCentre d’Immunologie de Marseille-Luminy, Aix Marseille Université, INSERM, CNRSInstitute of Medical Genetics and Pathology, Department of Urology, Department of Biomedicine, University Hospital BaselInstitut de Génétique et de Biologie Moléculaire et CellulaireInstitut de Génétique et de Biologie Moléculaire et CellulaireInstitut de Génétique et de Biologie Moléculaire et CellulaireInstitute of Medical Genetics and Pathology, Department of Urology, Department of Biomedicine, University Hospital BaselCentre d’Immunologie de Marseille-Luminy, Aix Marseille Université, INSERM, CNRSInstitut de Génétique et de Biologie Moléculaire et CellulaireInstitut de Génétique et de Biologie Moléculaire et CellulaireAbstract Prostate cancer is a heterogeneous disease with a slow progression and a highly variable clinical outcome. The tumor suppressor genes PTEN and TP53 are frequently mutated in prostate cancer and are predictive of early metastatic dissemination and unfavorable patient outcomes. The progression of solid tumors to metastasis is often associated with increased cell plasticity, but the complex events underlying TP53-loss-induced disease aggressiveness remain incompletely understood. Using genetically engineered mice, we show that Trp53 deficiency in Pten-null prostatic epithelial cells (PECs) does not impact early cell proliferation and neoplasia formation, nor growth arrest and senescence entry at a later time. However, Trp53-deficiency enhances invasive adenocarcinoma development and promotes metastatic cell dissemination. Importantly, our single-cell transcriptomic and chromatin accessibility analyses combined with histological examinations uncovered an epithelial cell population characterized by an induction of Jak/Stat3 signaling and displaying mesenchymal features. Moreover, we show that the transcriptomic signature of this cell population is prominent in tumors of patients with high-risk prostate cancer or metastatic disease. In addition, our in vivo and organoid-based experiments provide evidence that PEC plasticity occurs through bi-directional communication with cancer-associated fibroblasts (CAFs). Thus, our study demonstrates that p53 loss induces a protumorigenic crosstalk between PECs and CAFs, and identifies new vulnerabilities that might be targeted to limit cancer progression.https://doi.org/10.1038/s41419-025-07361-1 |
| spellingShingle | Darya Yanushko Beatriz German Falcon Rana El Bizri Despoina Pervizou Robin Dolgos Céline Keime Tao Ye Christelle Thibault-Carpentier Clementine Le Magnen Sandrine Henri Gilles Laverny Daniel Metzger p53-loss induced prostatic epithelial cell plasticity and invasion is driven by a crosstalk with the tumor microenvironment Cell Death and Disease |
| title | p53-loss induced prostatic epithelial cell plasticity and invasion is driven by a crosstalk with the tumor microenvironment |
| title_full | p53-loss induced prostatic epithelial cell plasticity and invasion is driven by a crosstalk with the tumor microenvironment |
| title_fullStr | p53-loss induced prostatic epithelial cell plasticity and invasion is driven by a crosstalk with the tumor microenvironment |
| title_full_unstemmed | p53-loss induced prostatic epithelial cell plasticity and invasion is driven by a crosstalk with the tumor microenvironment |
| title_short | p53-loss induced prostatic epithelial cell plasticity and invasion is driven by a crosstalk with the tumor microenvironment |
| title_sort | p53 loss induced prostatic epithelial cell plasticity and invasion is driven by a crosstalk with the tumor microenvironment |
| url | https://doi.org/10.1038/s41419-025-07361-1 |
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