Chromatin insulation orchestrates matrix metalloproteinase gene cluster expression reprogramming in aggressive breast cancer tumors
Llinàs-Arias, Pere (Institut d'Investigació Sanitària Illes Balears)
Ensenyat Méndez, Miquel (Institut d'Investigació Sanitària Illes Balears)
Íñiguez-Muñoz, Sandra (Cancer Institut d'Investigació Sanitària Illes Balears)
Orozco, Javier I. J (Saint John's Cancer Institute, Providence Saint John's Health Center, Santa Monica, CA, USA)
Valdez, Betsy (Saint John's Cancer Institute, Providence Saint John's Health Center, Santa Monica, CA, USA.)
Salomon, Matthew P. (University of Southern California, Los Angeles, USA)
Matsuba, Chikako (University of Southern California, Los Angeles, USA)
Solivellas-Pieras, Maria (Institut d'Investigació Sanitària Illes Balears)
Bedoya-López, Andrés F. (Institut d'Investigació Sanitària Illes Balears)
Sesé, Borja (Institut d'Investigació Sanitària Illes Balears)
Mezger, Anja (Science for Life Laboratory, Solna, Sweden)
Ormestad, Mattias (Science for Life Laboratory, Solna, Sweden)
Unzueta, Fernando (Universitat de Barcelona)
Strand, Siri H. (Stanford University School of Medicine, Stanford, USA)
Boiko, Alexander D. (Samuel Oschin Comprehensive Cancer Institute, Los Angeles, USA)
Hwang, E.Shelley (Duke University School of Medicine, Durham, USA)
Cortés, Javier (Universidad Europea de Madrid)
DiNome, Maggie L. (Duke University School of Medicine, Durham, USA)
Esteller, M (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Lupien, Mathieu (University of Toronto)
Marzese, Diego (Institut d'Investigació Sanitària Illes Balears)

Fecha:	2023
Resumen:	Background: Triple-negative breast cancer (TNBC) is an aggressive subtype that exhibits a high incidence of distant metastases and lacks targeted therapeutic options. Here we explored how the epigenome contributes to matrix metalloprotease (MMP) dysregulation impacting tumor invasion, which is the first step of the metastatic process. Methods: We combined RNA expression and chromatin interaction data to identify insulator elements potentially associated with MMP gene expression and invasion. We employed CRISPR/Cas9 to disrupt the CCCTC-Binding Factor (CTCF) binding site on an insulator element downstream of the MMP8 gene (IE8) in two TNBC cellular models. We characterized these models by combining Hi-C, ATAC-seq, and RNA-seq with functional experiments to determine invasive ability. The potential of our findings to predict the progression of ductal carcinoma in situ (DCIS), was tested in data from clinical specimens. Results: We explored the clinical relevance of an insulator element located within the Chr11q22. 2 locus, downstream of the MMP8 gene (IE8). This regulatory element resulted in a topologically associating domain (TAD) boundary that isolated nine MMP genes into two anti-correlated expression clusters. This expression pattern was associated with worse relapse-free (HR = 1. 57 [1. 06 − 2. 33]; p = 0. 023) and overall (HR = 2. 65 [1. 31 − 5. 37], p = 0. 005) survival of TNBC patients. After CRISPR/Cas9-mediated disruption of IE8, cancer cells showed a switch in the MMP expression signature, specifically downregulating the pro-invasive MMP1 gene and upregulating the antitumorigenic MMP8 gene, resulting in reduced invasive ability and collagen degradation. We observed that the MMP expression pattern predicts DCIS that eventually progresses into invasive ductal carcinomas (AUC = 0. 77, p < 0. 01). Conclusion: Our study demonstrates how the activation of an IE near the MMP8 gene determines the regional transcriptional regulation of MMP genes with opposing functional activity, ultimately influencing the invasive properties of aggressive forms of breast cancer.
Ayudas:	Instituto de Salud Carlos III PI22/01496 European Commission. Horizon 2020 824110
Derechos:	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.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	MMP1 ; MMP8 ; CTCF ; Insulator ; Chromatin ; Gene regulatory element ; Cis-regulatory element ; Breast cancer ; Invasion ; ATAC-seq ; RNA-seq ; Hi-C
Publicado en:	Molecular cancer, Vol. 22 Núm. 1 (november 2023) , ISSN 1476-4598

DOI: 10.1186/s12943-023-01906-8
PMID: 38017545

14 p, 7.4 MB

El registro aparece en las colecciones:
Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Instituto de Investigación contra la Leucemia Josep Carreras
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