1. Heterogeneous RNA editing and influence of ADAR2 on mesothelioma chemoresistance and the tumor microenvironment
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Hariharan, Ananya, Qi, Weihong, Rehrauer, Hubert, Wu, Licun, Ronner, Manuel, Wipplinger, Martin, Kresoja-Rakic, Jelena, Sun, Suna, Oton-Gonzalez, Lucia, Sculco, Marika, Serre-Beinier, Véronique, Meiller, Clément, Blanquart, Christophe, Fonteneau, Jean-François, Vrugt, Bart, Rüschoff, Jan Hendrik, Opitz, Isabelle, Jean, Didier, de Perrot, Marc, Felley-Bosco, Emanuela, University of Zurich, University hospital of Zurich [Zurich], Functional Genomics Center Zurich, Universität Zürich [Zürich] = University of Zurich (UZH)- Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), University Health Network, Hôpital Universitaire de Genève = University Hospitals of Geneva (HUG), Génomique fonctionnelle des tumeurs solides = Functional Genomics of Solid Tumors [CRC] (FunGeST), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Immunomodulation of the Tumor Microenvironment and Immunotherapy of Thoracic Cancers (CRCI2NA / Eq 1), Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers (CRCI2NA ), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Institute of Pathology and Molecular Pathology [Zurich], and Blanquart, Christophe
- Subjects
Mesothelioma ,10255 Clinic for Thoracic Surgery ,Adenosine Deaminase ,Mesothelioma, Malignant ,RNA-Binding Proteins ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,610 Medicine & health ,BRCA-associated protein 1 ,antifolate therapy ,mesothelioma ,RNA editing ,tumor microenvironment ,type-1 interferon ,Mice ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Drug Resistance, Neoplasm ,10049 Institute of Pathology and Molecular Pathology ,Tumor Microenvironment ,Animals ,RNA Editing - Abstract
We previously observed increased levels of adenosine-deaminase-acting-on-dsRNA (Adar)-dependent RNA editing during mesothelioma development in mice exposed to asbestos. The aim of this study was to characterize and assess the role of ADAR-dependent RNA editing in mesothelioma. We found that tumors and mesothelioma primary cultures have higher ADAR-mediated RNA editing compared to mesothelial cells. Unsupervised clustering of editing in different genomic regions revealed heterogeneity between tumor samples as well as mesothelioma primary cultures. ADAR2 expression levels are higher in BRCA1-associated protein 1 wild-type tumors, with corresponding changes in RNA editing in transcripts and 3'UTR. ADAR2 knockdown and rescue models indicated a role in cell proliferation, altered cell cycle, increased sensitivity to antifolate treatment, and type-1 interferon signaling upregulation, leading to changes in the microenvironment in vivo. Our data indicate that RNA editing contributes to mesothelioma heterogeneity and highlights an important role of ADAR2 not only in growth regulation in mesothelioma but also in chemotherapy response, in addition to regulating inflammatory response downstream of sensing nucleic acid structures., Molecular Oncology, 16 (22), ISSN:1574-7891
- Published
- 2022
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