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dc.contributor.author
Huna, Anda
dc.contributor.author
Flaman, Jean Michel
dc.contributor.author
Lodillinsky, Catalina
dc.contributor.author
Zhu, Kexin
dc.contributor.author
Makulyte, Gabriela
dc.contributor.author
Pakulska, Victoria
dc.contributor.author
Coute, Yohann
dc.contributor.author
Ruisseaux, Clémence
dc.contributor.author
Saintigny, Pierre
dc.contributor.author
Hernandez Vargas, Hector
dc.contributor.author
Defossez, Pierre Antoine
dc.contributor.author
Boissan, Mathieu
dc.contributor.author
Martin, Nadine
dc.contributor.author
Bernard, David
dc.date.available
2024-02-02T15:51:15Z
dc.date.issued
2023-12
dc.identifier.citation
Huna, Anda; Flaman, Jean Michel; Lodillinsky, Catalina; Zhu, Kexin; Makulyte, Gabriela; et al.; RSK3 switches cell fate: From stress-induced senescence to malignant progression; BioMed Central; Journal Of Experimental And Clinical Cancer Research; 42; 1; 12-2023; 1-16
dc.identifier.issn
1756-9966
dc.identifier.uri
http://hdl.handle.net/11336/225625
dc.description.abstract
Background: TGFβ induces several cell phenotypes including senescence, a stable cell cycle arrest accompanied by a secretory program, and epithelial-mesenchymal transition (EMT) in normal epithelial cells. During carcinogenesis cells lose the ability to undergo senescence in response to TGFβ but they maintain an EMT, which can contribute to tumor progression. Our aim was to identify mechanisms promoting TGFβ-induced senescence escape. Methods: In vitro experiments were performed with primary human mammary epithelial cells (HMEC) immortalized by hTert. For kinase library screen and modulation of gene expression retroviral transduction was used. To characterize gene expression, RNA microarray with GSEA analysis and RT-qPCR were used. For protein level and localization, Western blot and immunofluorescence were performed. For senescence characterization crystal violet assay, Senescence Associated-β-Galactosidase activity, EdU staining were conducted. To determine RSK3 partners FLAG-baited immunoprecipitation and mass spectrometry-based proteomic analyses were performed. Proteosome activity and proteasome enrichment assays were performed. To validate the role of RSK3 in human breast cancer, analysis of METABRIC database was performed. Murine intraductal xenografts using MCF10DCIS.com cells were carried out, with histological and immunofluorescence analysis of mouse tissue sections. Results: A screen with active kinases in HMECs upon TGFβ treatment identified that the serine threonine kinase RSK3, or RPS6KA2, a kinase mainly known to regulate cancer cell death including in breast cancer, reverted TGFβ-induced senescence. Interestingly, RSK3 expression decreased in response to TGFβ in a SMAD3-dependent manner, and its constitutive expression rescued SMAD3-induced senescence, indicating that a decrease in RSK3 itself contributes to TGFβ-induced senescence. Using transcriptomic analyses and affinity purification coupled to mass spectrometry-based proteomics, we unveiled that RSK3 regulates senescence by inhibiting the NF-κΒ pathway through the decrease in proteasome-mediated IκBα degradation. Strikingly, senescent TGFβ-treated HMECs display features of epithelial to mesenchymal transition (EMT) and during RSK3-induced senescence escaped HMECs conserve EMT features. Importantly, RSK3 expression is correlated with EMT and invasion, and inversely correlated with senescence and NF-κΒ in human claudin-low breast tumors and its expression enhances the formation of breast invasive tumors in the mouse mammary gland. Conclusions: We conclude that RSK3 switches cell fate from senescence to malignancy in response to TGFβ signaling.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
BioMed Central
dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by/2.5/ar/
dc.subject
BREAST TUMOR
dc.subject
CELLULAR SENESCENCE
dc.subject
EPITHELIAL-MESENCHYMAL TRANSITION
dc.subject
TGFΒ
dc.subject.classification
Patología
dc.subject.classification
Medicina Básica
dc.subject.classification
CIENCIAS MÉDICAS Y DE LA SALUD
dc.title
RSK3 switches cell fate: From stress-induced senescence to malignant progression
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2024-01-25T14:00:52Z
dc.journal.volume
42
dc.journal.number
1
dc.journal.pagination
1-16
dc.journal.pais
Reino Unido
dc.journal.ciudad
Londres
dc.description.fil
Fil: Huna, Anda. Equipe Labellisée La Ligue Contre Le Cancer; Francia. Cancer Research Center of Lyon; Francia
dc.description.fil
Fil: Flaman, Jean Michel. Equipe Labellisée La Ligue Contre Le Cancer; Francia. Cancer Research Center of Lyon; Francia
dc.description.fil
Fil: Lodillinsky, Catalina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina. Sorbonne University; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina
dc.description.fil
Fil: Zhu, Kexin. Cancer Research Center Of Lyon; Francia. Equipe Labellisée La Ligue Contre Le Cancer; Francia
dc.description.fil
Fil: Makulyte, Gabriela. Equipe Labellisée La Ligue Contre Le Cancer; Francia. Cancer Research Center Of Lyon; Francia
dc.description.fil
Fil: Pakulska, Victoria. Universite Grenoble Alpes; Francia
dc.description.fil
Fil: Coute, Yohann. Universite Grenoble Alpes; Francia
dc.description.fil
Fil: Ruisseaux, Clémence. Cancer Research Center Of Lyon; Francia
dc.description.fil
Fil: Saintigny, Pierre. Cancer Research Center Of Lyon; Francia
dc.description.fil
Fil: Hernandez Vargas, Hector. Cancer Research Center Of Lyon; Francia
dc.description.fil
Fil: Defossez, Pierre Antoine. Epigenetics and Cell Fate Centre; Francia
dc.description.fil
Fil: Boissan, Mathieu. INSERM UMR_S 938; Francia
dc.description.fil
Fil: Martin, Nadine. Cancer Research Center Of Lyon; Francia. Equipe Labellisée La Ligue Contre Le Cancer; Francia
dc.description.fil
Fil: Bernard, David. Cancer Research Center Of Lyon; Francia. Equipe Labellisée La Ligue Contre Le Cancer; Francia
dc.journal.title
Journal Of Experimental And Clinical Cancer Research
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://jeccr.biomedcentral.com/articles/10.1186/s13046-023-02909-5
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1186/s13046-023-02909-5
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