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

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• dc.contributor.author Fuertes, Guillem
• dc.contributor.author Valle Pérez, Beatriz del
• dc.contributor.author Pastor Ruiz, Javier
• dc.contributor.author Andrades, Evelyn
• dc.contributor.author Peña Arranz, Raúl, 1976-
• dc.contributor.author García de Herreros, Antonio
• dc.contributor.author Duñach, Mireia
• dc.date.accessioned 2023-09-15T06:19:34Z
• dc.date.available 2023-09-15T06:19:34Z
• dc.date.issued 2023
• dc.description.abstract 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.
• dc.description.sponsorship 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).
• dc.format.mimetype application/pdf
• dc.identifier.citation Fuertes G, Del Valle-Pérez B, Pastor J, Andrades E, Peña R, García de Herreros A, Duñach M. Noncanonical Wnt signaling promotes colon tumor growth, chemoresistance and tumor fibroblast activation. EMBO Rep. 2023;24(4):e54895. DOI: 10.15252/embr.202254895
• dc.identifier.doi http://dx.doi.org/10.15252/embr.202254895
• dc.identifier.issn 1469-221X
• dc.identifier.uri http://hdl.handle.net/10230/57866
• dc.language.iso eng
• dc.publisher EMBO Press
• dc.relation.ispartof EMBO Rep. 2023;24(4):e54895
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-099719-B-100
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-104698RB-I00
• dc.rights © 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.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
• dc.subject.keyword Snail1
• dc.subject.keyword Cancer stem cell
• dc.subject.keyword Chemoresistance
• dc.subject.keyword Metastasis
• dc.subject.keyword Noncanonical Wnt
• dc.title Noncanonical Wnt signaling promotes colon tumor growth, chemoresistance and tumor fibroblast activation
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion