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

Sánchez-Tilló, Ester; Pedrosa, Leire; Vila, Ingrid; Chen, Yongxu; Gyorffy, Balázs; Sánchez-Moral, Lidia; Siles, Laura; Lozano, Juan José; Esteve-Codina, Anna; Darling, Douglas S.; Cuatrecasas, Miriam; Castells, Antoni; Maurel, Joan; Postigo, Antonio

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

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dc.contributor.author Sánchez-Tilló, Ester
dc.contributor.author Pedrosa, Leire
dc.contributor.author Vila, Ingrid
dc.contributor.author Chen, Yongxu
dc.contributor.author Gyorffy, Balázs
dc.contributor.author Sánchez-Moral, Lidia
dc.contributor.author Siles, Laura
dc.contributor.author Lozano, Juan José
dc.contributor.author Esteve-Codina, Anna
dc.contributor.author Darling, Douglas S.
dc.contributor.author Cuatrecasas, Miriam
dc.contributor.author Castells, Antoni
dc.contributor.author Maurel, Joan
dc.contributor.author Postigo, Antonio
dc.date.accessioned 2024-02-09T07:49:53Z
dc.date.available 2024-02-09T07:49:53Z
dc.date.issued 2023
dc.description.abstract 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.
dc.description.sponsorship The experimental work in this study was funded by independent grants to EST and AP. Funding for EST came from the Spanish National Institute of Health Carlos III (ISCIII) through the Miguel Servet Program (grant CP13/00200) and the National Plan of Scientific and Technical Research and Innovation Plan 2013-2016 cofinanced by the European Regional Development Fund of the European Union Commission (EUC-ERDF) (grants AES2018 and PI18/00244). Grants to AP that funded independent parts of the study originated from the Spanish Association Against Cancer (AECC; grant PROYE19040POST_001), Olga Torres Foundation (biannual grant A-2019/2020), Catalan Agency for Management of University and Research Grants (AGAUR) (grants 2017-SGR-1174 and 2021-SGR-01328), and the Spanish State Research Agency (AEI) of the Spanish Ministry of Science and Innovation (MICINN) (grant PID2020-116338RB-I00) as part of MICINN’s National Scientific and Technical Research and Innovation 2021-2023 Plans, which are cofinanced by the EUC-ERDF. The salaries of both EST and IV were funded by a Miguel Servet contract (reference MS13/00200) and a grant (CPII18/00022) from ISCIII to EST. LP was funded by the AECC (project GCTRA16015SEDA). YC is the recipient of a doctoral scholarship from the China Scholarship Council (202008440322). BG was financed by the 2020-1.1.6-JÖVŐ-2021-00013 and 2020-4.1.1-TKP2020 grants of the Ministry for Innovation and Technology in Hungary. LSM is the recipient of a doctoral scholarship from the University Lecturer Training (FPU) Program (FPU14/06217) of the Spanish Ministry of Universities. AEC’s salary is covered by grant PT17/0009/0019 from ISCIII (MICINN, cofunded by the ERDF) to CNAG-CRG.
dc.format.mimetype application/pdf
dc.identifier.citation Sánchez-Tilló E, Pedrosa L, Vila I, Chen Y, Győrffy B, Sánchez-Moral L, Siles L, Lozano JJ, Esteve-Codina A, Darling DS, Cuatrecasas M, Castells A, Maurel J, Postigo A. The EMT factor ZEB1 paradoxically inhibits EMT in BRAF-mutant carcinomas. JCI Insight. 2023 Oct 23;8(20):e164629. DOI: 10.1172/jci.insight.164629
dc.identifier.doi http://dx.doi.org/10.1172/jci.insight.164629
dc.identifier.issn 2379-3708
dc.identifier.uri http://hdl.handle.net/10230/59044
dc.language.iso eng
dc.publisher American Society for Clinical Investigation
dc.relation.ispartof JCI Insight. 2023 Oct 23;8(20):e164629
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-116338RB-I00
dc.rights © 2023, Sánchez-Tilló et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject.keyword Colorectal cancer
dc.subject.keyword Gastroenterology
dc.subject.keyword Oncology
dc.title The EMT factor ZEB1 paradoxically inhibits EMT in BRAF-mutant carcinomas
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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