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Hand2 Delineates Mesothelium Progenitors and Is Reactivated in Mesothelioma

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Hand2 Delineates Mesothelium Progenitors and Is Reactivated in Mesothelioma bioRxiv preprint doi: https://doi.org/10.1101/2020.11.11.355693; this version posted November 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Hand2 delineates mesothelium progenitors and is reactivated in mesothelioma Karin D. Prummel1,2, Helena L. Crowell2,3, Susan Nieuwenhuize1,2, Eline C. Brombacher2, Stephan Daetwyler4, Charlotte Soneson2,3, Jelena Kresoja-Rakic1,5, Manuel Ronner5, Agnese Kocere1,2, Alexander Ernst6, Zahra Labbaf7, David E. Clouthier8, Anthony B. Firulli9, Héctor Sánchez-Iranzo6, Rebecca O’Rourke1, Erez Raz7, Nadia Mercader6, Alexa Burger1,2, Emanuela Felley-Bosco5, Jan Huisken4,10, Mark D. Robinson2,3, Christian Mosimann1,* 1Department of Pediatrics, Section of Developmental Biology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA. 2Department of Molecular Life Sciences, University of Zurich, Zürich, Switzerland. 3 SIB Swiss Institute of Bioinformatics, University of Zurich, Zürich, Switzerland. 4Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany. 5Laboratory of Molecular Oncology, Department of Thoracic Surgery, University Hospital Zurich, Zürich, Switzerland. 6Institute of Anatomy, University of Bern, Bern, Switzerland. 7Institute for Cell Biology, ZMBE, Muenster, Germany. 8Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. 9Herman B Wells Center for Pediatric Research, Departments of Pediatrics, Anatomy and Medical and Molecular Genetics, Indiana Medical School, Indianapolis, IN, USA. 10Morgridge Institute for Research, Madison, Wisconsin, USA. *correspondence to: [email protected] Abstract The mesothelium forms epithelial membranes that line the bodies cavities and surround the internal organs. Mesothelia widely contribute to organ homeostasis and regeneration, and their dysregulation can result in congenital anomalies of the viscera, ventral wall defects, and mesothelioma tumors. Nonetheless, the embryonic ontogeny and developmental regulation of mesothelium formation has remained uncharted. Here, we combine genetic lineage tracing, in toto live imaging, and single-cell transcriptomics in zebrafish to track mesothelial progenitor origins from the lateral plate mesoderm (LPM). Our single-cell analysis uncovers a post- gastrulation gene expression signature centered on hand2 that delineates distinct progenitor populations within the forming LPM. Combining gene expression analysis and imaging of transgenic reporter zebrafish embryos, we chart the origin of mesothelial progenitors to the lateral-most, hand2-expressing LPM and confirm evolutionary conservation in mouse. Our time-lapse imaging of transgenic hand2 reporter embryos captures zebrafish mesothelium formation, documenting the coordinated cell movements that form pericardium and visceral and parietal peritoneum. We establish that the primordial germ cells migrate associated with the forming mesothelium as ventral migration boundary. Functionally, hand2 mutants fail to close the ventral mesothelium due to perturbed migration of mesothelium progenitors. Analyzing mouse and human mesothelioma tumors hypothesized to emerge from transformed mesothelium, we find de novo expression of LPM-associated transcription factors, and in particular of Hand2, indicating the re-initiation of a developmental transcriptional program in mesothelioma. Taken together, our work outlines a genetic and developmental signature of mesothelial origins centered around Hand2, contributing to our understanding of mesothelial pathologies and mesothelioma. Introduction As a key feature of the vertebrate body plan, the contributes to a multitude of downstream cell fates mesothelium is composed of several continuous, including smooth muscles and fibroblasts during epithelial monolayers surrounding the internal organs organogenesis, tissue homeostasis, and (visceral mesothelium) and lining the body cavities regeneration (Carmona et al., 2018; Koopmans and (parietal mesothelium). The mesothelium provides a Rinkevich, 2018; Rinkevich et al., 2012). While protective layer against invasive microorganisms, mesothelium-lined body cavities are a fundamental produces trait across bilaterian animals (Hartenstein and serous fluid that both decreases friction of moving Mandal, 2006; Monahan-Earley et al., 2013; Technau organs, and enables the transport of cells and and Scholz, 2003), little is known about how the nutrients across serosal cavities (Mutsaers, 2002; vertebrate mesothelium lineage initially emerges Mutsaers and Wilkosz, 2007). Moreover, cell tracking during development. studies have established that the mesothelium The embryonic mesothelium, also called coelomic Prummel et al. Hand2 delineates mesothelium 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.11.11.355693; this version posted November 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. epithelium after establishing its baso-apical result in pathologies including intra-abdominal organ polarization, is a highly dynamic cell layer that adhesion (Tsai et al., 2018), serosal fibrosis undergoes epithelial-to-mesenchymal transition (Mutsaers et al., 2015), pericarditis (Chiabrando et (EMT) during development and seeds mesenchymal al., 2020), and mesothelioma tumors (Carbone et al., cells to underlying tissues (Carmona et al., 2018; 2019; Yap et al., 2017). Malignant mesothelioma is a Rinkevich et al., 2012). Several prior observations tie rapidly fatal solid tumor that can arise within the mesothelial lineage origins to the lateral plate visceral or parietal mesothelia, predominantly as the mesoderm (LPM) (Ahn et al., 2002; Carmona et al., result of environmental exposure to asbestos 2016; Winters et al., 2012), a mesodermal progenitor (Carbone et al., 2019; Felley-Bosco and Macfarlane, territory that forms at the periphery of the early 2018; Odgerel et al., 2017; Wagner et al., 1962; Yap vertebrate embryo (Prummel et al., 2020). In et al., 2017). While mesothelioma cases are vertebrates, the coelomic cavity forms stereotypically increasing globally despite regulatory means to curb by splitting the LPM into dorsal and ventral layers the use of causative agents, treatment remains (Onimaru et al., 2011). A subset of cells within both limited (Hinz and Heasley, 2019; Yap et al., 2017). layers differentiates into polarized epithelial cells that Presenting predominantly as epithelioid, form visceral (splanchnic) mesothelial layers and sarcomatoid, and biphasic phenotypes, malignant parietal (somatic) mesothelial layers (Funayama et mesothelioma frequently harbor genetic alterations al., 1999; Sadler and Feldkamp, 2008; Sheng, 2015). affecting the tumor suppressors BAP1, NF2, Ultimately, the coelom in amniotes spans from the CDKN2AB, and TP53 (Bueno et al., 2016; Cheng et neck to the abdomen and outlines four main body al., 1994; Hmeljak et al., 2018; Quetel et al., 2020; compartments: two pleural cavities (around the Tate et al., 2019). Nonetheless, the cell of origin and lungs), a pericardiac cavity (around the heart), and a the underlying aberrant molecular mechanisms peritoneal (abdominal) cavity, each with their leading to mesothelioma remain uncertain. associated mesothelial layers (Fig. 1A). In addition to the mesothelium, the LPM forms a Representative for teleosts, zebrafish feature vast array of downstream cell fates that include the mesothelium-lined cardiac and abdominal cavities. cardiovascular system, blood, kidneys, and limb Which territories within the emerging LPM initially connective tissue (Prummel et al., 2020). How the harbor the mesothelial progenitors, how and when the LPM partitions into its diverse fates and what mesothelium diverges from other LPM lineages, and regulatory programs specify the individual progenitor how the visceral and parietal layers form remain fields remains unclear. Emerging as a dedicated uncharted. mesendoderm domain, the post-gastrulation LPM Embryonic studies of the mesothelium have segments into recognizable bilateral territories predominantly focused on developmental stages after discernible by the expression of several transcription the coelomic epithelium has formed. Several genes, factor genes including Scl/Tal1, Lmo2, Pax2a, including Mesothelin (Msln), Gata4, Tbx18, Tcf21, Nkx2.5, and Hand1/2 (Chal and Pourquié, 2017; and Wilms Tumor 1 (Wt1), have enabled labeling and Davidson and Zon, 2004; Prummel et al., 2020; genetic lineage tracing of mesothelial lineages in Takasato and Little, 2015). dHand/Hand2, encoding mouse and chick (Alghamdi et al., 2020; Ariza et al., a conserved basic helix-loop-helix transcription 2016; Chau et al., 2014; Delgado et al., 2014; factor, is expressed during segmentation stages in Rinkevich et al., 2012). The Wt1-expressing coelomic the most laterally positioned LPM progenitors in epithelium contributes to the mature mesothelium, amphioxus and zebrafish (Onimaru et al., 2011; fibroblasts, stellate cells, smooth muscles, and white Perens et al., 2016; Prummel et al., 2019). In the adipose tissue associated with the gastrointestinal developing mouse embryo, Hand2 expression has tract, liver, lungs, urogenital system,
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