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The mesothelium lines body cavities and surrounds internal organs, widely contributing to homeostasis and regeneration. Mesothelium disruptions cause visceral anomalies and mesothelioma tumors. Nonetheless, the embryonic emergence of mesothelia remains incompletely understood. Here, we track mesothelial origins in the lateral plate mesoderm (LPM) using zebrafish. Single-cell transcriptomics uncovers a post-gastrulation gene expression signature centered on hand2 in distinct LPM progenitor cells. We map mesothelial progenitors to lateral-most, hand2-expressing LPM and confirm conservation in mouse. Time-lapse imaging of zebrafish hand2 reporter embryos captures mesothelium formation including pericardium, visceral, and parietal peritoneum. We find primordial germ cells migrate with the forming mesothelium as ventral migration boundary. Functionally, hand2 loss disrupts mesothelium formation with reduced progenitor cells and perturbed migration. In mouse and human mesothelioma, we document expression of LPM-associated transcription factors including Hand2, suggesting re-initiation of a developmental program. Our data connects mesothelium development to Hand2, expanding our understanding of mesothelial pathologies. We thank Single Cell Discoveries for executing the single-cell RNA-sequencing, as well as the Center for Microscopy and Image Analysis (ZMB) and the Cytometry Facility (FCF) of the University of Zurich for technical support and equipment. We also thank Dr. Deborah Yelon, Dr. Richard M. White, Dr. Charles K. Kaufman, and the members of the Mosimann lab for critical input on the manuscript. Species schematics in Figs. 1 and 7 were adjusted from templates provided by PhyloPic (phylopic.org). Zebrafish schematics in Fig. 1 were adjusted from BioRender (biorender.com). This work has been supported by Swiss National Science Foundation (SNSF) professorship PP00P3_139093, SNSF R’Equip grant 316030_150838 (Light Sheet Fluorescence Microscopy), SNSF CRSII5_180345, a Marie Curie Career Integration Grant from the European Commission (CIG PCIG14-GA-2013-631984), the Canton of Zurich, the UZH Foundation for Research in Science and the Humanities, the Swiss Heart Foundation, the ZUNIV FAN/ UZH Alumni, the University of Colorado School of Medicine, Department of Pediatrics and Section of Developmental Biology, and the Helen and Arthur E. Johnson Foundation and Children’s Hospital Colorado Foundation to C.M.; the Swiss Bridge Foundation to A.B. and C.M; a UZH CanDoc to S.N.; EuFishBioMed and Company of Biologists travel fellowships to K.D.P.; SNSF postdoc mobility fellowship P400PB_191057 to J.K.R.; Human Frontier Science Program (HFSP) long-term postdoctoral fellowship LT000078/ 2016 to S.R.N.; SNSF grant 320030_182690 and Stiftung für Angewandte Krebsforschung to E.F.B.; SNSF 310030L_182575 and ERC Starting Grant 2013 337703 to N.M.; SNSF grants 310030_175841 and CRSII5_177208 and University of Zurich’s Research Priority Program Evolution in Action to M.D.R.. Sí

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