Structural disruption of BAF chromatin remodeller impairs neuroblastoma metastasis by reverting an invasiveness epigenomic program
Jiménez Jiménez, Carlos (Vall d'Hebron Institut de Recerca (VHIR))
Antonelli, Roberta (Vall d'Hebron Institut de Recerca (VHIR))
Nadal-Ribelles, Mariona (Universitat Pompeu Fabra)
Devis-Jauregui, Laura (Institut d'Investigació Biomèdica de Bellvitge)
Latorre, Pablo (Universitat Pompeu Fabra)
Solé Serra, Carme (Universitat Pompeu Fabra)
Masanas, Marc (Vall d'Hebron Institut de Recerca (VHIR))
Molero-Valenzuela, Adrià (Vall d'Hebron Institut de Recerca (VHIR))
Soriano, Aroa (Vall d'Hebron Institut de Recerca (VHIR))
Sánchez de Toledo Codin, Josep (Institut Català d'Oncologia)
Llobet-Navas, David (Instituto de Salud Carlos III)
Roma, Josep (Vall d'Hebron Institut de Recerca (VHIR))
Posas, Francesc (Universitat Pompeu Fabra)
de Nadal, Eulàlia (Universitat Pompeu Fabra)
Gallego, Soledad (Hospital Universitari Vall d'Hebron)
Moreno Martin Retortillo, Lucas (Hospital Universitari Vall d'Hebron)
Segura, Miguel F. (Vall d'Hebron Institut de Recerca (VHIR))
Universitat Autònoma de Barcelona. Departament de Pediatria, Obstetrícia i Ginecologia i de Medicina Preventiva i Salut Pública

Data:	2022
Resum:	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. 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. 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. 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.
Ajuts:	Instituto de Salud Carlos III PI17/00564 Instituto de Salud Carlos III PI20/00530 Agencia Estatal de Investigación PID2021-124723NB-C21 Agencia Estatal de Investigación PID2021-124723NB-C22
Nota:	Altres ajuts: 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); State Research Agency (institutional funding through Unidad de Excelencia María de Maeztu, CEX2018-000792-M)
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Epigenetics ; Epigenomics ; Cancer ; Neuroblastoma ; Chromatin remodelling ; SWI/SNF ; Metastasis
Publicat a:	Molecular cancer, Vol. 21, Num. 1 (september 2022) , ISSN 1476-4598

DOI: 10.1186/s12943-022-01643-4
PMID: 36057593

17 p, 10.2 MB

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