Increased genomic instability and reshaping of tissue microenvironment underlie oncogenic properties of Arid1a mutations.

Autor: D'Ambrosio A; Laboratory of stem cells and cancer genomics, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy.; SEMM, University of Milan, 20142 Milan, Italy., Bressan D; Laboratory of stem cells and cancer genomics, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy., Ferracci E; Laboratory of stem cells and cancer genomics, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy., Carbone F; Unità Operativa Multizonale di Anatomia Patologica, APSS, 38122 Trento, Italy., Mulè P; Department of Experimental Oncology, European Institute of Oncology (IEO), IRCCS, 20139 Milan, Italy., Rossi F; Department of Experimental Oncology, European Institute of Oncology (IEO), IRCCS, 20139 Milan, Italy., Barbieri C; Department of Experimental Oncology, European Institute of Oncology (IEO), IRCCS, 20139 Milan, Italy., Sorrenti E; Laboratory of stem cells and cancer genomics, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy., Fiaccadori G; Laboratory of stem cells and cancer genomics, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy., Detone T; Unità Operativa Multizonale di Anatomia Patologica, APSS, 38122 Trento, Italy., Vezzoli E; Department of Biomedical sciences for Health, University of Milan, 20133 Milan, Italy., Bianchi S; Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), 20139 Milan, Italy., Sartori C; Unità Operativa Multizonale di Anatomia Patologica, APSS, 38122 Trento, Italy., Corso S; Department of Oncology, University of Torino, 10060 Candiolo, Italy.; Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Italy., Fukuda A; Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan., Bertalot G; Unità Operativa Multizonale di Anatomia Patologica, APSS, 38122 Trento, Italy.; Centre for Medical Sciences-CISMed, University of Trento, 38122 Trento, Italy., Falqui A; Department of Physics, University of Milan, 20133 Milan, Italy., Barbareschi M; Unità Operativa Multizonale di Anatomia Patologica, APSS, 38122 Trento, Italy.; Centre for Medical Sciences-CISMed, University of Trento, 38122 Trento, Italy., Romanel A; Laboratory of Bioinformatics and Computational Genomics, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy., Pasini D; Department of Experimental Oncology, European Institute of Oncology (IEO), IRCCS, 20139 Milan, Italy.; Department of Health Sciences, University of Milan, 20142 Milan, Italy., Chiacchiera F; Laboratory of stem cells and cancer genomics, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2024 Mar 15; Vol. 10 (11), pp. eadh4435. Date of Electronic Publication: 2024 Mar 15.
DOI: 10.1126/sciadv.adh4435
Abstrakt: Oncogenic mutations accumulating in many chromatin-associated proteins have been identified in different tumor types. With a mutation rate from 10 to 57%, ARID1A has been widely considered a tumor suppressor gene. However, whether this role is mainly due to its transcriptional-related activities or its ability to preserve genome integrity is still a matter of intense debate. Here, we show that ARID1A is largely dispensable for preserving enhancer-dependent transcriptional regulation, being ARID1B sufficient and required to compensate for ARID1A loss. We provide in vivo evidence that ARID1A is mainly required to preserve genomic integrity in adult tissues. ARID1A loss primarily results in DNA damage accumulation, interferon type I response activation, and chronic inflammation leading to tumor formation. Our data suggest that in healthy tissues, the increased genomic instability that follows ARID1A mutations and the selective pressure imposed by the microenvironment might result in the emergence of aggressive, possibly immune-resistant, tumors.
Databáze: MEDLINE
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