Noncanonical Wnt signaling promotes colon tumor growth, chemoresistance and tumor fibroblast activation

Colon tumors of the mesenchymal subtype have the lowest overall survival. Snail1 is essential for the acquisition of this phenotype, characterized by increased tumor stemness and invasion, and high resistance to chemotherapy. Here, we find that Snail1 expression in colon tumor cells is dependent on...

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Autores: Fuertes, Guillem, Valle Pérez, Beatriz del, Pastor Ruiz, Javier, Andrades, Evelyn, Peña Arranz, Raúl, 1976-, García de Herreros, Antonio, Duñach, Mireia
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10230/57866
Acceso en línea:http://hdl.handle.net/10230/57866
http://dx.doi.org/10.15252/embr.202254895
Access Level:acceso abierto
Palabra clave:Snail1
Cancer stem cell
Chemoresistance
Metastasis
Noncanonical Wnt
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spelling Noncanonical Wnt signaling promotes colon tumor growth, chemoresistance and tumor fibroblast activationFuertes, GuillemValle Pérez, Beatriz delPastor Ruiz, JavierAndrades, EvelynPeña Arranz, Raúl, 1976-García de Herreros, AntonioDuñach, MireiaSnail1Cancer stem cellChemoresistanceMetastasisNoncanonical WntColon tumors of the mesenchymal subtype have the lowest overall survival. Snail1 is essential for the acquisition of this phenotype, characterized by increased tumor stemness and invasion, and high resistance to chemotherapy. Here, we find that Snail1 expression in colon tumor cells is dependent on an autocrine noncanonical Wnt pathway. Accordingly, depletion of Ror2, the co-receptor for noncanonical Wnts such as Wnt5a, potently decreases Snail1 expression. Wnt5a, Ror2, and Snail1 participate in a self-stimulatory feedback loop since Wnt5a increases its own synthesis in a Ror2- and Snail1-dependent fashion. This Wnt5a/Ror2/Snail1 axis controls tumor invasion, chemoresistance, and formation of tumor spheres. It also stimulates TGFβ synthesis; consequently, tumor cells expressing Snail1 are more efficient in activating cancer-associated fibroblasts than the corresponding controls. Ror2 downmodulation or inhibition of the Wnt5a pathway decreases Snail1 expression in primary colon tumor cells and their ability to form tumors and liver metastases. Finally, the expression of SNAI1, ROR2, and WNT5A correlates in human colon and other tumors. These results identify inhibition of the noncanonical Wnt pathway as a putative colon tumor therapy.This study was funded by grants RTI2018-099719-B-100, awarded by Ministerio de Ciencia, Innovación y Universidades -Agencia Estatal de Investigación (Retos de Investigación) and FEDER (to MD) and PID2019-104698RB-I00 funded by MCIN/ AEI/10.13039/501100011033 (to AGH). We also acknowledge support from ICREA Academia. GF was recipient of a predoctoral fellowship from FPI (MINECO).EMBO Press202320232023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/57866http://dx.doi.org/10.15252/embr.202254895reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésEMBO Rep. 2023;24(4):e54895info:eu-repo/grantAgreement/ES/2PE/RTI2018-099719-B-100info:eu-repo/grantAgreement/ES/2PE/PID2019-104698RB-I00© 2023 The Authors. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.http://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:10230/578662026-05-29T05:05:01Z
dc.title.none.fl_str_mv Noncanonical Wnt signaling promotes colon tumor growth, chemoresistance and tumor fibroblast activation
title Noncanonical Wnt signaling promotes colon tumor growth, chemoresistance and tumor fibroblast activation
spellingShingle Noncanonical Wnt signaling promotes colon tumor growth, chemoresistance and tumor fibroblast activation
Fuertes, Guillem
Snail1
Cancer stem cell
Chemoresistance
Metastasis
Noncanonical Wnt
title_short Noncanonical Wnt signaling promotes colon tumor growth, chemoresistance and tumor fibroblast activation
title_full Noncanonical Wnt signaling promotes colon tumor growth, chemoresistance and tumor fibroblast activation
title_fullStr Noncanonical Wnt signaling promotes colon tumor growth, chemoresistance and tumor fibroblast activation
title_full_unstemmed Noncanonical Wnt signaling promotes colon tumor growth, chemoresistance and tumor fibroblast activation
title_sort Noncanonical Wnt signaling promotes colon tumor growth, chemoresistance and tumor fibroblast activation
dc.creator.none.fl_str_mv Fuertes, Guillem
Valle Pérez, Beatriz del
Pastor Ruiz, Javier
Andrades, Evelyn
Peña Arranz, Raúl, 1976-
García de Herreros, Antonio
Duñach, Mireia
author Fuertes, Guillem
author_facet Fuertes, Guillem
Valle Pérez, Beatriz del
Pastor Ruiz, Javier
Andrades, Evelyn
Peña Arranz, Raúl, 1976-
García de Herreros, Antonio
Duñach, Mireia
author_role author
author2 Valle Pérez, Beatriz del
Pastor Ruiz, Javier
Andrades, Evelyn
Peña Arranz, Raúl, 1976-
García de Herreros, Antonio
Duñach, Mireia
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv Snail1
Cancer stem cell
Chemoresistance
Metastasis
Noncanonical Wnt
topic Snail1
Cancer stem cell
Chemoresistance
Metastasis
Noncanonical Wnt
description Colon tumors of the mesenchymal subtype have the lowest overall survival. Snail1 is essential for the acquisition of this phenotype, characterized by increased tumor stemness and invasion, and high resistance to chemotherapy. Here, we find that Snail1 expression in colon tumor cells is dependent on an autocrine noncanonical Wnt pathway. Accordingly, depletion of Ror2, the co-receptor for noncanonical Wnts such as Wnt5a, potently decreases Snail1 expression. Wnt5a, Ror2, and Snail1 participate in a self-stimulatory feedback loop since Wnt5a increases its own synthesis in a Ror2- and Snail1-dependent fashion. This Wnt5a/Ror2/Snail1 axis controls tumor invasion, chemoresistance, and formation of tumor spheres. It also stimulates TGFβ synthesis; consequently, tumor cells expressing Snail1 are more efficient in activating cancer-associated fibroblasts than the corresponding controls. Ror2 downmodulation or inhibition of the Wnt5a pathway decreases Snail1 expression in primary colon tumor cells and their ability to form tumors and liver metastases. Finally, the expression of SNAI1, ROR2, and WNT5A correlates in human colon and other tumors. These results identify inhibition of the noncanonical Wnt pathway as a putative colon tumor therapy.
publishDate 2023
dc.date.none.fl_str_mv 2023
2023
2023
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 http://hdl.handle.net/10230/57866
http://dx.doi.org/10.15252/embr.202254895
url http://hdl.handle.net/10230/57866
http://dx.doi.org/10.15252/embr.202254895
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv EMBO Rep. 2023;24(4):e54895
info:eu-repo/grantAgreement/ES/2PE/RTI2018-099719-B-100
info:eu-repo/grantAgreement/ES/2PE/PID2019-104698RB-I00
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv EMBO Press
publisher.none.fl_str_mv EMBO Press
dc.source.none.fl_str_mv 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
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