Structural disruption of BAF chromatin remodeller impairs neuroblastoma metastasis by reverting an invasiveness epigenomic program

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• dc.contributor.author Jiménez, Carlos
• dc.contributor.author Antonelli, Roberta
• dc.contributor.author Nadal Ribelles, Mariona, 1984-
• dc.contributor.author Devis-Jauregui, Laura
• dc.contributor.author Latorre Doménech, Pablo, 1993-
• dc.contributor.author Solé, Carme
• dc.contributor.author Masanas, Marc
• dc.contributor.author Molero-Valenzuela, Adrià
• dc.contributor.author Soriano, Aroa
• dc.contributor.author Sánchez de Toledo, Josep
• dc.contributor.author Llobet-Navas, David
• dc.contributor.author Roma, Josep
• dc.contributor.author Posas Garriga, Francesc
• dc.contributor.author Nadal Clanchet, Eulàlia de
• dc.contributor.author Gallego, Soledad
• dc.contributor.author Moreno, Lucas
• dc.contributor.author Segura, Miguel F.
• dc.date.accessioned 2022-11-15T07:08:39Z
• dc.date.available 2022-11-15T07:08:39Z
• dc.date.issued 2022
• dc.description.abstract Background: Epigenetic programming during development is essential for determining cell lineages, and alterations in this programming contribute to the initiation of embryonal tumour development. In neuroblastoma, neural crest progenitors block their course of natural differentiation into sympathoadrenergic cells, leading to the development of aggressive and metastatic paediatric cancer. Research of the epigenetic regulators responsible for oncogenic epigenomic networks is crucial for developing new epigenetic-based therapies against these tumours. Mammalian switch/sucrose non-fermenting (mSWI/SNF) ATP-dependent chromatin remodelling complexes act genome-wide translating epigenetic signals into open chromatin states. The present study aimed to understand the contribution of mSWI/SNF to the oncogenic epigenomes of neuroblastoma and its potential as a therapeutic target. Methods: Functional characterisation of the mSWI/SNF complexes was performed in neuroblastoma cells using proteomic approaches, loss-of-function experiments, transcriptome and chromatin accessibility analyses, and in vitro and in vivo assays. Results: Neuroblastoma cells contain three main mSWI/SNF subtypes, but only BRG1-associated factor (BAF) complex disruption through silencing of its key structural subunits, ARID1A and ARID1B, impairs cell proliferation by promoting cell cycle blockade. Genome-wide chromatin remodelling and transcriptomic analyses revealed that BAF disruption results in the epigenetic repression of an extensive invasiveness-related expression program involving integrins, cadherins, and key mesenchymal regulators, thereby reducing adhesion to the extracellular matrix and the subsequent invasion in vitro and drastically inhibiting the initiation and growth of neuroblastoma metastasis in vivo. Conclusions: We report a novel ATPase-independent role for the BAF complex in maintaining an epigenomic program that allows neuroblastoma invasiveness and metastasis, urging for the development of new BAF pharmacological structural disruptors for therapeutic exploitation in metastatic neuroblastoma.
• dc.description.sponsorship This work was funded by Instituto de Salud Carlos III (CP16/00006, PI17/00564 and PI20/00530 to MFS and MS17/00063 to DL-N); Asociación Española Contra el Cáncer (LABAE18009SEGU to MFS, LABAE19004LLOB to DL-N, PROYE18010POSA to FP); Generalitat de Catalunya (2017FI_B_00095 to CJ, 2017SGR799 to FP and EdN; institutional funding through CERCA Programme); La Caixa Foundation (LCF/BQ/PR20/11770001 to MN-R); Spanish Ministry of Economy and Competitiveness (PID2021-124723NB-C21 to FP and PID2021-124723NB-C22 to EdN); Spanish Ministry of Science, Innovation and Universities (institutional funding through Centres of Excellence Severo Ochoa Award); State Research Agency (institutional funding through Unidad de Excelencia María de Maeztu, CEX2018-000792-M); and the Catalan Institution for Research and Advanced Studies (Academia awards to EdN and FP). Funding was also received from NEN association; Joan Petit foundation; Asociación Pulseras Candela foundation; and the Rotary Clubs of Barcelona Eixample, Barcelona Diagonal, Santa Coloma de Gramanet, München-Blutenburg, Deutschland Gemeindienst, and others from Barcelona and its province.
• dc.format.mimetype application/pdf
• dc.identifier.citation Jiménez C, Antonelli R, Nadal-Ribelles M, Devis-Jauregui L, Latorre P, Solé C, Masanas M, Molero-Valenzuela A, Soriano A, Sánchez de Toledo J, Llobet-Navas D, Roma J, Posas F, de Nadal E, Gallego S, Moreno L, Segura MF. Structural disruption of BAF chromatin remodeller impairs neuroblastoma metastasis by reverting an invasiveness epigenomic program. Mol Cancer. 2022 Sep 3;21(1):175. DOI: 10.1186/s12943-022-01643-4
• dc.identifier.doi http://dx.doi.org/10.1186/s12943-022-01643-4
• dc.identifier.issn 1476-4598
• dc.identifier.uri http://hdl.handle.net/10230/54845
• dc.language.iso eng
• dc.publisher BioMed Central
• dc.relation.ispartof Mol Cancer. 2022 Sep 3;21(1):175
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2021-124723NB-C21
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2021-124723NB-C22
• dc.rights © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Cancer
• dc.subject.keyword Chromatin remodelling
• dc.subject.keyword Epigenetics
• dc.subject.keyword Epigenomics
• dc.subject.keyword Metastasis
• dc.subject.keyword Neuroblastoma
• dc.subject.keyword SWI/SNF
• dc.title Structural disruption of BAF chromatin remodeller impairs neuroblastoma metastasis by reverting an invasiveness epigenomic program
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion