P53-loss induced prostatic epithelial cell plasticity and invasion is driven by a crosstalk with the tumor microenvironment

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 soli...

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Detalhes bibliográficos
Autores: Yanushko, Darya, German Falcon, Beatriz, El Bizri, Rana, Pervizou, Despoina, Dolgos, Robin, Keime, Céline, Ye, Tao, Thibault Carpentier, Christelle, Le Magnen, Clementine, Henri, Sandrine, Laverny, Gilles, Metzger, Daniel
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Recursos:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/218879
Acesso em linha:https://hdl.handle.net/2445/218879
Access Level:acceso abierto
Palavra-chave:Càncer de pròstata
Mutació (Biologia)
Prostate cancer
Mutation (Biology)
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spelling P53-loss induced prostatic epithelial cell plasticity and invasion is driven by a crosstalk with the tumor microenvironmentYanushko, DaryaGerman Falcon, BeatrizEl Bizri, RanaPervizou, DespoinaDolgos, RobinKeime, CélineYe, TaoThibault Carpentier, ChristelleLe Magnen, ClementineHenri, SandrineLaverny, GillesMetzger, DanielCàncer de pròstataMutació (Biologia)Prostate cancerMutation (Biology)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.Springer Science and Business Media LLC2025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/218879Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1038/s41419-025-07361-1Cell Death & Disease, 2025, vol. 16https://doi.org/10.1038/s41419-025-07361-1cc-by (c) Yanushko, Darya et al., 2025http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/2188792026-05-27T06:46:51Z
dc.title.none.fl_str_mv P53-loss induced prostatic epithelial cell plasticity and invasion is driven by a crosstalk with the tumor microenvironment
title P53-loss induced prostatic epithelial cell plasticity and invasion is driven by a crosstalk with the tumor microenvironment
spellingShingle P53-loss induced prostatic epithelial cell plasticity and invasion is driven by a crosstalk with the tumor microenvironment
Yanushko, Darya
Càncer de pròstata
Mutació (Biologia)
Prostate cancer
Mutation (Biology)
title_short 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_sort P53-loss induced prostatic epithelial cell plasticity and invasion is driven by a crosstalk with the tumor microenvironment
dc.creator.none.fl_str_mv Yanushko, Darya
German Falcon, Beatriz
El Bizri, Rana
Pervizou, Despoina
Dolgos, Robin
Keime, Céline
Ye, Tao
Thibault Carpentier, Christelle
Le Magnen, Clementine
Henri, Sandrine
Laverny, Gilles
Metzger, Daniel
author Yanushko, Darya
author_facet Yanushko, Darya
German Falcon, Beatriz
El Bizri, Rana
Pervizou, Despoina
Dolgos, Robin
Keime, Céline
Ye, Tao
Thibault Carpentier, Christelle
Le Magnen, Clementine
Henri, Sandrine
Laverny, Gilles
Metzger, Daniel
author_role author
author2 German Falcon, Beatriz
El Bizri, Rana
Pervizou, Despoina
Dolgos, Robin
Keime, Céline
Ye, Tao
Thibault Carpentier, Christelle
Le Magnen, Clementine
Henri, Sandrine
Laverny, Gilles
Metzger, Daniel
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Càncer de pròstata
Mutació (Biologia)
Prostate cancer
Mutation (Biology)
topic Càncer de pròstata
Mutació (Biologia)
Prostate cancer
Mutation (Biology)
description 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.
publishDate 2025
dc.date.none.fl_str_mv 2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/218879
url https://hdl.handle.net/2445/218879
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1038/s41419-025-07361-1
Cell Death & Disease, 2025, vol. 16
https://doi.org/10.1038/s41419-025-07361-1
dc.rights.none.fl_str_mv cc-by (c) Yanushko, Darya et al., 2025
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Yanushko, Darya et al., 2025
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Springer Science and Business Media LLC
publisher.none.fl_str_mv Springer Science and Business Media LLC
dc.source.none.fl_str_mv Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.811543

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