The EMT factor ZEB1 paradoxically inhibits EMT in BRAF-mutant carcinomas

Despite being in the same pathway, mutations of KRAS and BRAF in colorectal carcinomas (CRCs) determine distinct progression courses. ZEB1 induces an epithelial-to-mesenchymal transition (EMT) and is associated with worse progression in most carcinomas. Using samples from patients with CRC, mouse mo...

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Authors: Sanchez Tillo, E., Pedrosa, Leire, Vila, I., Chen, Yao, Gyorffy, B., Sánchez Moral, L., Siles Mena, Laura, Lozano Salvatella, Juan José, Esteve Codina, A., Darling, Douglas S., Cuatrecasas Freixas, Miriam, Castells Garangou, Antoni, Maurel Santasusana, Joan, Postigo, Antonio
Format: article
Status:Published version
Publication Date:2023
Country:España
Institution:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repository:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/208724
Online Access:https://hdl.handle.net/2445/208724
Access Level:Open access
Keyword:Càncer
Transducció de senyal cel·lular
Carcinoma
Signal Transduction
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spelling The EMT factor ZEB1 paradoxically inhibits EMT in BRAF-mutant carcinomasSanchez Tillo, E.Pedrosa, LeireVila, I.Chen, YaoGyorffy, B.Sánchez Moral, L.Siles Mena, LauraLozano Salvatella, Juan JoséEsteve Codina, A.Darling, Douglas S.Cuatrecasas Freixas, MiriamCastells Garangou, AntoniMaurel Santasusana, JoanPostigo, AntonioCàncerTransducció de senyal cel·lularCarcinomaSignal TransductionDespite being in the same pathway, mutations of KRAS and BRAF in colorectal carcinomas (CRCs) determine distinct progression courses. ZEB1 induces an epithelial-to-mesenchymal transition (EMT) and is associated with worse progression in most carcinomas. Using samples from patients with CRC, mouse models of KrasG12D and BrafV600E CRC, and a Zeb1-deficient mouse, we show that ZEB1 had opposite functions in KRAS-and BRAF-mutant CRCs. In KrasG12D CRCs, ZEB1 was correlated with a worse prognosis and a higher number of larger and undifferentiated (mesenchymal or EMT-like) tumors. Surprisingly, in BrafV600E CRC, ZEB1 was associated with better prognosis; fewer, smaller, and more differentiated (reduced EMT) primary tumors; and fewer metastases. ZEB1 was positively correlated in KRAS-mutant CRC cells and negatively in BRAF-mutant CRC cells with gene signatures for EMT, cell proliferation and survival, and ERK signaling. On a mechanistic level, ZEB1 knockdown in KRAS-mutant CRC cells increased apoptosis and reduced clonogenicity and anchorage-independent growth; the reverse occurred in BRAFV600E CRC cells. ZEB1 is associated with better prognosis and reduced EMT signature in patients harboring BRAF CRCs. These data suggest that ZEB1 can function as a tumor suppressor in BRAF-mutant CRCs, highlighting the importance of considering the KRAS/BRAF mutational background of CRCs in therapeutic strategies targeting ZEB1/EMT.American Society for Clinical Investigation2024202420232024info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion19 p.application/pdfapplication/pdfhttps://hdl.handle.net/2445/208724Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1172/jci.insight.164629Jci Insight, 2023, vol. 8, num. 20, p. e164629https://doi.org/10.1172/jci.insight.164629cc by (c) Sánchez Tilló, Ester et al., 2023http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:recercat.cat:2445/2087242026-05-29T05:05:01Z
dc.title.none.fl_str_mv The EMT factor ZEB1 paradoxically inhibits EMT in BRAF-mutant carcinomas
title The EMT factor ZEB1 paradoxically inhibits EMT in BRAF-mutant carcinomas
spellingShingle The EMT factor ZEB1 paradoxically inhibits EMT in BRAF-mutant carcinomas
Sanchez Tillo, E.
Càncer
Transducció de senyal cel·lular
Carcinoma
Signal Transduction
title_short The EMT factor ZEB1 paradoxically inhibits EMT in BRAF-mutant carcinomas
title_full The EMT factor ZEB1 paradoxically inhibits EMT in BRAF-mutant carcinomas
title_fullStr The EMT factor ZEB1 paradoxically inhibits EMT in BRAF-mutant carcinomas
title_full_unstemmed The EMT factor ZEB1 paradoxically inhibits EMT in BRAF-mutant carcinomas
title_sort The EMT factor ZEB1 paradoxically inhibits EMT in BRAF-mutant carcinomas
dc.creator.none.fl_str_mv Sanchez Tillo, E.
Pedrosa, Leire
Vila, I.
Chen, Yao
Gyorffy, B.
Sánchez Moral, L.
Siles Mena, Laura
Lozano Salvatella, Juan José
Esteve Codina, A.
Darling, Douglas S.
Cuatrecasas Freixas, Miriam
Castells Garangou, Antoni
Maurel Santasusana, Joan
Postigo, Antonio
author Sanchez Tillo, E.
author_facet Sanchez Tillo, E.
Pedrosa, Leire
Vila, I.
Chen, Yao
Gyorffy, B.
Sánchez Moral, L.
Siles Mena, Laura
Lozano Salvatella, Juan José
Esteve Codina, A.
Darling, Douglas S.
Cuatrecasas Freixas, Miriam
Castells Garangou, Antoni
Maurel Santasusana, Joan
Postigo, Antonio
author_role author
author2 Pedrosa, Leire
Vila, I.
Chen, Yao
Gyorffy, B.
Sánchez Moral, L.
Siles Mena, Laura
Lozano Salvatella, Juan José
Esteve Codina, A.
Darling, Douglas S.
Cuatrecasas Freixas, Miriam
Castells Garangou, Antoni
Maurel Santasusana, Joan
Postigo, Antonio
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Càncer
Transducció de senyal cel·lular
Carcinoma
Signal Transduction
topic Càncer
Transducció de senyal cel·lular
Carcinoma
Signal Transduction
description Despite being in the same pathway, mutations of KRAS and BRAF in colorectal carcinomas (CRCs) determine distinct progression courses. ZEB1 induces an epithelial-to-mesenchymal transition (EMT) and is associated with worse progression in most carcinomas. Using samples from patients with CRC, mouse models of KrasG12D and BrafV600E CRC, and a Zeb1-deficient mouse, we show that ZEB1 had opposite functions in KRAS-and BRAF-mutant CRCs. In KrasG12D CRCs, ZEB1 was correlated with a worse prognosis and a higher number of larger and undifferentiated (mesenchymal or EMT-like) tumors. Surprisingly, in BrafV600E CRC, ZEB1 was associated with better prognosis; fewer, smaller, and more differentiated (reduced EMT) primary tumors; and fewer metastases. ZEB1 was positively correlated in KRAS-mutant CRC cells and negatively in BRAF-mutant CRC cells with gene signatures for EMT, cell proliferation and survival, and ERK signaling. On a mechanistic level, ZEB1 knockdown in KRAS-mutant CRC cells increased apoptosis and reduced clonogenicity and anchorage-independent growth; the reverse occurred in BRAFV600E CRC cells. ZEB1 is associated with better prognosis and reduced EMT signature in patients harboring BRAF CRCs. These data suggest that ZEB1 can function as a tumor suppressor in BRAF-mutant CRCs, highlighting the importance of considering the KRAS/BRAF mutational background of CRCs in therapeutic strategies targeting ZEB1/EMT.
publishDate 2023
dc.date.none.fl_str_mv 2023
2024
2024
2024
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/2445/208724
url https://hdl.handle.net/2445/208724
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/10.1172/jci.insight.164629
Jci Insight, 2023, vol. 8, num. 20, p. e164629
https://doi.org/10.1172/jci.insight.164629
dc.rights.none.fl_str_mv cc by (c) Sánchez Tilló, Ester et al., 2023
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by (c) Sánchez Tilló, Ester et al., 2023
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 19 p.
application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Society for Clinical Investigation
publisher.none.fl_str_mv American Society for Clinical Investigation
dc.source.none.fl_str_mv Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869423705851953152
score 15,81155

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