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1. European Epidemiology of Pleural Mesothelioma—Real-Life Data From a Joint Analysis of the Mesoscape Database of the European Thoracic Oncology Platform and the European Society of Thoracic Surgery Mesothelioma Database

Author

Stahel, Rolf, Hiltbrunner, Anita, Kammler, Rosita, Marti, Nesa, Ruepp, Barbara, Dafni, Urania, Tsourti, Zoi, Zygoura, Panagiota, Vervita, Katerina, Dimopoulou, Georgia, Andriakopoulou, Charitini, Stavrou, Androniki, Rüschoff, Jan H., Haberecker, Martina, Dettwiler, Susanne, Prutek, Fabiola, Mittmann, Christiane, Opitz, Isabelle, Vrugt, Bart, Friess, Martina, Matter, Alessandra, Spichiger-Häusermann, Chloé, Kirschner, Michaela B., Felley-Bosco, Emanuela, Baas, Paul, Monkhorst, Kim, Nackaerts, Kristiaan, Verbeken, Eric, Weynand, Birgit, Nafteux, Philippe, Moons, Johnny, Peeters, Liesbet, Ampollini, Luca, Tiseo, Marcello, Silini, Enrico Maria, Gnetti, Letizia, Carbognani, Paolo, de Perrot, Marc, Bavaghar-Zaeimi, Fatemeh, Brcic, Luka, Samarzija, Miroslav, Seiwerth, Sven, Jakopovic, Marko, Nadal, Ernest, Cardenal, Felipe, Llatjos, Roger, Lorente, Susana, Syrigos, Konstantinos, Vamvakaris, Ioannis, Tsimpoukis, Sotirios, Boura, Paraskevi, Gray, Steven G., Finn, Stephen P., Nur, Mutaz Mohammed, Baird, Anne-Marie, Barr, Martin P., Cuffe, Sinead, Gately, Kathy, Aerts, Joachim, Thüsen, Jan von der, Bille, Andrea, Passani, Stefano, Brunelli, Alessandro, Curioni-Fontecedro, Alessandra, von der Thüsen, Jan, Kammler, Roswitha, Peters, Solange, Stahel, Rolf A., and Falcoz, Pierre-Emmanuel

Published
2023
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2. Expression of phosphorylated ribosomal protein S6 in mesothelioma patients - correlation with clinico-pathological characteristics and outcome: results from the European Thoracic Oncology Platform (ETOP) Mesoscape project

Author

Rüschoff, Jan Hendrik, Haberecker, Martina, Tsourti, Zoi, Nackaerts, Kristiaan, de Perrot, Marc, Brcic, Luka, Nadal, Ernest, Tsimpoukis, Sotirios, Gray, Steven G., Ampollini, Luca, Aerts, Joachim G., Felley-Bosco, Emanuela, Kirschner, Michaela B., Monkhorst, Kim, Weynand, Birgit, Bavaghar-Zaeimi, Fatemeh, Samarzija, Miroslav, Llatjos, Roger, Finn, Stephen P., Silini, Enrico, von der Thüsen, Jan, Marti, Nesa, Vervita, Karerina, Kammler, Roswitha, Peters, Solange, Stahel, Rolf A., Baas, Paul, and Opitz, Isabelle

Published
2022
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4. Mesothelioma: Scientific clues for prevention, diagnosis, and therapy.

Author

Carbone, Michele, Adusumilli, Prasad S, Alexander, H Richard, Baas, Paul, Bardelli, Fabrizio, Bononi, Angela, Bueno, Raphael, Felley-Bosco, Emanuela, Galateau-Salle, Francoise, Jablons, David, Mansfield, Aaron S, Minaai, Michael, de Perrot, Marc, Pesavento, Patricia, Rusch, Valerie, Severson, David T, Taioli, Emanuela, Tsao, Anne, Woodard, Gavitt, Yang, Haining, Zauderer, Marjorie G, and Pass, Harvey I

Subjects
Pleura, Humans, Mesothelioma, Pleural Neoplasms, Genetic Predisposition to Disease, Asbestos, Ubiquitin Thiolesterase, Tumor Suppressor Proteins, Diagnostic Errors, Prognosis, Combined Modality Therapy, Pneumonectomy, Incidence, Inhalation Exposure, Occupational Exposure, Germ-Line Mutation, International Cooperation, United States, Australia, Europe, Molecular Targeted Therapy, Carcinogenesis, Biomarkers, Tumor, Global Burden of Disease, Antineoplastic Agents, Immunological, BRCA1-associated protein 1, asbestos, cancer syndromes, chromothripsis, gene-environment interaction, immunotherapy, mesothelioma, Lung, Rare Diseases, Lung Cancer, Cancer, Prevention, Good Health and Well Being, Clinical Sciences, Public Health and Health Services, Oncology & Carcinogenesis
Abstract

Mesothelioma affects mostly older individuals who have been occupationally exposed to asbestos. The global mesothelioma incidence and mortality rates are unknown, because data are not available from developing countries that continue to use large amounts of asbestos. The incidence rate of mesothelioma has decreased in Australia, the United States, and Western Europe, where the use of asbestos was banned or strictly regulated in the 1970s and 1980s, demonstrating the value of these preventive measures. However, in these same countries, the overall number of deaths from mesothelioma has not decreased as the size of the population and the percentage of old people have increased. Moreover, hotspots of mesothelioma may occur when carcinogenic fibers that are present in the environment are disturbed as rural areas are being developed. Novel immunohistochemical and molecular markers have improved the accuracy of diagnosis; however, about 14% (high-resource countries) to 50% (developing countries) of mesothelioma diagnoses are incorrect, resulting in inadequate treatment and complicating epidemiological studies. The discovery that germline BRCA1-asssociated protein 1 (BAP1) mutations cause mesothelioma and other cancers (BAP1 cancer syndrome) elucidated some of the key pathogenic mechanisms, and treatments targeting these molecular mechanisms and/or modulating the immune response are being tested. The role of surgery in pleural mesothelioma is controversial as it is difficult to predict who will benefit from aggressive management, even when local therapies are added to existing or novel systemic treatments. Treatment outcomes are improving, however, for peritoneal mesothelioma. Multidisciplinary international collaboration will be necessary to improve prevention, early detection, and treatment.

Published
2019

5. Hand2 delineates mesothelium progenitors and is reactivated in mesothelioma

Author

Prummel, Karin D., Crowell, Helena L., Nieuwenhuize, Susan, Brombacher, Eline C., Daetwyler, Stephan, Soneson, Charlotte, Kresoja-Rakic, Jelena, Kocere, Agnese, Ronner, Manuel, Ernst, Alexander, Labbaf, Zahra, Clouthier, David E., Firulli, Anthony B., Sánchez-Iranzo, Héctor, Naganathan, Sundar R., O’Rourke, Rebecca, Raz, Erez, Mercader, Nadia, Burger, Alexa, Felley-Bosco, Emanuela, Huisken, Jan, Robinson, Mark D., and Mosimann, Christian

Published
2022
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7. Correction to: Expression of phosphorylated ribosomal protein S6 in mesothelioma patients - correlation with clinico-pathological characteristics and outcome: results from the European Thoracic Oncology Platform (ETOP) Mesoscape project

Author

Rüschoff, Jan Hendrik, Haberecker, Martina, Tsourti, Zoi, Nackaerts, Kristiaan, de Perrot, Marc, Brcic, Luka, Nadal, Ernest, Tsimpoukis, Sotirios, Gray, Steven G., Ampollini, Luca, Aerts, Joachim G., Felley-Bosco, Emanuela, Kirschner, Michaela B., Monkhorst, Kim, Weynand, Birgit, Bavaghar-Zaeimi, Fatemeh, Samarzija, Miroslav, Llatjos, Roger, Finn, Stephen P., Silini, Enrico, von der Thüsen, Jan, Marti, Nesa, Vervita, Karerina, Kammler, Roswitha, Peters, Solange, Stahel, Rolf A., Baas, Paul, and Opitz, Isabelle

Published
2022
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11. European Epidemiology of Pleural Mesothelioma—Real-Life Data From a Joint Analysis of the Mesoscape Database of the European Thoracic Oncology Platform and the European Society of Thoracic Surgery Mesothelioma Database

Author

Opitz, Isabelle, primary, Bille, Andrea, additional, Dafni, Urania, additional, Nackaerts, Kristiaan, additional, Ampollini, Luca, additional, de Perrot, Marc, additional, Brcic, Luka, additional, Nadal, Ernest, additional, Syrigos, Konstantinos, additional, Gray, Steven G., additional, Aerts, Joachim, additional, Curioni-Fontecedro, Alessandra, additional, Rüschoff, Jan H., additional, Monkhorst, Kim, additional, Weynand, Birgit, additional, Silini, Enrico Maria, additional, Bavaghar-Zaeimi, Fatemeh, additional, Jakopovic, Marko, additional, Llatjos, Roger, additional, Tsimpoukis, Sotirios, additional, Finn, Stephen P., additional, von der Thüsen, Jan, additional, Marti, Nesa, additional, Dimopoulou, Georgia, additional, Kammler, Roswitha, additional, Peters, Solange, additional, Stahel, Rolf A., additional, Falcoz, Pierre-Emmanuel, additional, Brunelli, Alessandro, additional, Baas, Paul, additional, Stahel, Rolf, additional, Hiltbrunner, Anita, additional, Kammler, Rosita, additional, Ruepp, Barbara, additional, Tsourti, Zoi, additional, Zygoura, Panagiota, additional, Vervita, Katerina, additional, Andriakopoulou, Charitini, additional, Stavrou, Androniki, additional, Haberecker, Martina, additional, Dettwiler, Susanne, additional, Prutek, Fabiola, additional, Mittmann, Christiane, additional, Opitz, Isabelle, additional, Vrugt, Bart, additional, Friess, Martina, additional, Matter, Alessandra, additional, Spichiger-Häusermann, Chloé, additional, Kirschner, Michaela B., additional, Felley-Bosco, Emanuela, additional, Verbeken, Eric, additional, Nafteux, Philippe, additional, Moons, Johnny, additional, Peeters, Liesbet, additional, Tiseo, Marcello, additional, Gnetti, Letizia, additional, Carbognani, Paolo, additional, Samarzija, Miroslav, additional, Seiwerth, Sven, additional, Cardenal, Felipe, additional, Lorente, Susana, additional, Vamvakaris, Ioannis, additional, Boura, Paraskevi, additional, Nur, Mutaz Mohammed, additional, Baird, Anne-Marie, additional, Barr, Martin P., additional, Cuffe, Sinead, additional, Gately, Kathy, additional, Thüsen, Jan von der, additional, and Passani, Stefano, additional

Published
2023
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14. Supplementary figure s4 from Antagonizing the Hedgehog Pathway with Vismodegib Impairs Malignant Pleural Mesothelioma Growth In Vivo by Affecting Stroma

Author

Meerang, Mayura, primary, Bérard, Karima, primary, Felley-Bosco, Emanuela, primary, Lauk, Olivia, primary, Vrugt, Bart, primary, Boss, Andreas, primary, Kenkel, David, primary, Broggini-Tenzer, Angela, primary, Stahel, Rolf A., primary, Arni, Stephan, primary, Weder, Walter, primary, and Opitz, Isabelle, primary

Published
2023
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15. Supplementary table 1 from Antagonizing the Hedgehog Pathway with Vismodegib Impairs Malignant Pleural Mesothelioma Growth In Vivo by Affecting Stroma

Author

Meerang, Mayura, primary, Bérard, Karima, primary, Felley-Bosco, Emanuela, primary, Lauk, Olivia, primary, Vrugt, Bart, primary, Boss, Andreas, primary, Kenkel, David, primary, Broggini-Tenzer, Angela, primary, Stahel, Rolf A., primary, Arni, Stephan, primary, Weder, Walter, primary, and Opitz, Isabelle, primary

Published
2023
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16. Data from Functional Genomic Screen in Mesothelioma Reveals that Loss of Function of BRCA1-Associated Protein 1 Induces Chemoresistance to Ribonucleotide Reductase Inhibition

Author

Okonska, Agata, primary, Bühler, Saskja, primary, Rao, Vasundhara, primary, Ronner, Manuel, primary, Blijlevens, Maxime, primary, van der Meulen-Muileman, Ida H., primary, de Menezes, Renee X., primary, Wipplinger, Martin, primary, Oehl, Kathrin, primary, Smit, Egbert F., primary, Weder, Walter, primary, Stahel, Rolf A., primary, Penengo, Lorenza, primary, van Beusechem, Victor W., primary, and Felley-Bosco, Emanuela, primary

Published
2023
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17. Supplementary figure legends from Antagonizing the Hedgehog Pathway with Vismodegib Impairs Malignant Pleural Mesothelioma Growth In Vivo by Affecting Stroma

Author

Meerang, Mayura, primary, Bérard, Karima, primary, Felley-Bosco, Emanuela, primary, Lauk, Olivia, primary, Vrugt, Bart, primary, Boss, Andreas, primary, Kenkel, David, primary, Broggini-Tenzer, Angela, primary, Stahel, Rolf A., primary, Arni, Stephan, primary, Weder, Walter, primary, and Opitz, Isabelle, primary

Published
2023
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18. Data from Antagonizing the Hedgehog Pathway with Vismodegib Impairs Malignant Pleural Mesothelioma Growth In Vivo by Affecting Stroma

Author

Meerang, Mayura, primary, Bérard, Karima, primary, Felley-Bosco, Emanuela, primary, Lauk, Olivia, primary, Vrugt, Bart, primary, Boss, Andreas, primary, Kenkel, David, primary, Broggini-Tenzer, Angela, primary, Stahel, Rolf A., primary, Arni, Stephan, primary, Weder, Walter, primary, and Opitz, Isabelle, primary

Published
2023
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19. Supplementary Data from Functional Genomic Screen in Mesothelioma Reveals that Loss of Function of BRCA1-Associated Protein 1 Induces Chemoresistance to Ribonucleotide Reductase Inhibition

Author

Okonska, Agata, primary, Bühler, Saskja, primary, Rao, Vasundhara, primary, Ronner, Manuel, primary, Blijlevens, Maxime, primary, van der Meulen-Muileman, Ida H., primary, de Menezes, Renee X., primary, Wipplinger, Martin, primary, Oehl, Kathrin, primary, Smit, Egbert F., primary, Weder, Walter, primary, Stahel, Rolf A., primary, Penengo, Lorenza, primary, van Beusechem, Victor W., primary, and Felley-Bosco, Emanuela, primary

Published
2023
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20. Mesothelioma Heterogeneity : Potential Mechanisms

Author

Felley-Bosco, Emanuela

Abstract

Mesothelioma is a rare aggressive cancer that develops from the mesothelium. Recent molecular analyses have defined four different types of mesothelioma based on gene expression and two major molecularly-defined groups based on prognosis. In this volume, potential mechanisms causing this heterogeneity are explored. The different chapters include heterogeneity learned from experimental animal models in NF2/Hippo pathway signaling, stem cell signaling pathways, the tumor microenvironment, and micro RNA secretome. Novel aspects deserving attention such as the implication of long, non-coding RNA in disease heterogeneity are described. The volume also includes the description of tools useful to address some specific questions such as an assessment of the copy number variations of two tumor suppressors frequently mutated in mesothelioma or an investigation of Macrophage Inhibition Factor signaling in mesothelioma.

Published
2018

26. Supplementary Data from Gemcitabine Synergizes with Immune Checkpoint Inhibitors and Overcomes Resistance in a Preclinical Model and Mesothelioma Patients

Author

Tallón de Lara, Paulino, primary, Cecconi, Virginia, primary, Hiltbrunner, Stefanie, primary, Yagita, Hideo, primary, Friess, Martina, primary, Bode, Beata, primary, Opitz, Isabelle, primary, Vrugt, Bart, primary, Weder, Walter, primary, Stolzmann, Paul, primary, Felley-Bosco, Emanuela, primary, Stahel, Rolf A., primary, Tischler, Verena, primary, Britschgi, Christian, primary, Soldini, Davide, primary, van den Broek, Maries, primary, and Curioni-Fontecedro, Alessandra, primary

Published
2023
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31. Defining and targeting tumor-associated macrophages in malignant mesothelioma

Author

Wu, Licun, primary, Kohno, Mikihiro, additional, Murakami, Junichi, additional, Zia, Amin, additional, Allen, Jonathan, additional, Yun, Hana, additional, Chan, Meilin, additional, Baciu, Cristina, additional, Liu, Mingyao, additional, Serre-Beinier, Veronique, additional, De Palma, Michele, additional, Felley-Bosco, Emanuela, additional, Yeung, Jonathan, additional, Pugh, Trevor J., additional, and de Perrot, Marc, additional

Published
2023
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35. Heterogeneous RNA editing and influence of ADAR2 on mesothelioma chemoresistance and the tumor microenvironment

Author

Hariharan, Ananya, primary, Qi, Weihong, additional, Rehrauer, Hubert, additional, Wu, Licun, additional, Ronner, Manuel, additional, Wipplinger, Martin, additional, Kresoja‐Rakic, Jelena, additional, Sun, Suna, additional, Oton‐Gonzalez, Lucia, additional, Sculco, Marika, additional, Serre‐Beinier, Véronique, additional, Meiller, Clément, additional, Blanquart, Christophe, additional, Fonteneau, Jean‐François, additional, Vrugt, Bart, additional, Rüschoff, Jan Hendrik, additional, Opitz, Isabelle, additional, Jean, Didier, additional, de Perrot, Marc, additional, and Felley‐Bosco, Emanuela, additional

Published
2022
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37. Hand2 delineates mesothelium progenitors and is reactivated in mesothelioma

Author

Prummel, Karin D, Crowell, Helena L, Nieuwenhuize, Susan, Brombacher, Eline C, Daetwyler, Stephan, Soneson, Charlotte, Kresoja-Rakic, Jelena, Kocere, Agnese, Ronner, Manuel, Ernst, Alexander, Labbaf, Zahra, Clouthier, David E, Firulli, Anthony B, Sánchez-Iranzo, Héctor, Naganathan, Sundar R, O’Rourke, Rebecca, Raz, Erez, Mercader, Nadia, Burger, Alexa, Felley-Bosco, Emanuela, Huisken, Jan, Robinson, Mark D, Mosimann, Christian, University of Zurich, Mosimann, Christian, Swiss National Science Foundation, and Swiss Heart Foundation

Subjects
Mesothelioma, Multidisciplinary, animal structures, 10255 Clinic for Thoracic Surgery, General Physics and Astronomy, 610 Medicine & health, 1600 General Chemistry, Genetics and Molecular Biology, General Chemistry, Zebrafish Proteins, General Biochemistry, Genetics and Molecular Biology, Epithelium, 10124 Institute of Molecular Life Sciences, 3100 General Physics and Astronomy, UFSP13-7 Evolution in Action: From Genomes to Ecosystems, Mice, 1300 General Biochemistry, Genetics and Molecular Biology, embryonic structures, General Biochemistry, Basic Helix-Loop-Helix Transcription Factors, Animals, 570 Life sciences, biology, Zebrafish, Transcription Factors
Abstract

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

Published
2022

40. Heterogeneity of RNA editing in mesothelioma and how RNA editing enzyme ADAR2 affects mesothelioma cell growth, response to chemotherapy and tumor microenvironment

Author

Hariharan, Ananya, primary, Qi, Weihong, additional, Rehrauer, Hubert, additional, Wu, Licun, additional, Ronner, Manuel, additional, Wipplinger, Martin, additional, Kresoja-Rakic, Jelena, additional, Sun, Suna, additional, Oton-Gonzales, Lucia, additional, Sculco, Marika, additional, Serre-Beinier, Veronique, additional, Meiller, Clement, additional, Blanquart, Christophe, additional, Fonteneau, Jean-Francois, additional, Vrugt, Bart, additional, Rueschoff, Jan H, additional, Opitz, Isabelle, additional, JEAN, Didier, additional, de Perrot, Marc, additional, and Felley-Bosco, Emanuela, additional

Published
2022
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41. Medical and Surgical Care of Patients With Mesothelioma and Their Relatives Carrying Germline BAP1 Mutations

Author

Carbone, Michele, primary, Pass, Harvey I., additional, Ak, Guntulu, additional, Alexander, H. Richard, additional, Baas, Paul, additional, Baumann, Francine, additional, Blakely, Andrew M., additional, Bueno, Raphael, additional, Bzura, Aleksandra, additional, Cardillo, Giuseppe, additional, Churpek, Jane E., additional, Dianzani, Irma, additional, De Rienzo, Assunta, additional, Emi, Mitsuru, additional, Emri, Salih, additional, Felley-Bosco, Emanuela, additional, Fennell, Dean A., additional, Flores, Raja M., additional, Grosso, Federica, additional, Hayward, Nicholas K., additional, Hesdorffer, Mary, additional, Hoang, Chuong D., additional, Johansson, Peter A., additional, Kindler, Hedy L., additional, Kittaneh, Muaiad, additional, Krausz, Thomas, additional, Mansfield, Aaron, additional, Metintas, Muzaffer, additional, Minaai, Michael, additional, Mutti, Luciano, additional, Nielsen, Maartje, additional, O’Byrne, Kenneth, additional, Opitz, Isabelle, additional, Pastorino, Sandra, additional, Pentimalli, Francesca, additional, de Perrot, Marc, additional, Pritchard, Antonia, additional, Ripley, Robert Taylor, additional, Robinson, Bruce, additional, Rusch, Valerie, additional, Taioli, Emanuela, additional, Takinishi, Yasutaka, additional, Tanji, Mika, additional, Tsao, Anne S., additional, Tuncer, A. Murat, additional, Walpole, Sebastian, additional, Wolf, Andrea, additional, Yang, Haining, additional, Yoshikawa, Yoshie, additional, Zolondick, Alicia, additional, Schrump, David S., additional, and Hassan, Raffit, additional

Published
2022
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47. Defining and targeting tumor-associated macrophages in malignant mesothelioma.

Author

Licun Wu, Kohno, Mikihiro, Murakami, Junichi, Zia, Amin, Allen, Jonathan, Hana Yun, Meilin Chan, Baciu, Cristina, Mingyao Liu, Serre-Beinier, Veronique, De Palma, Michele, Felley-Bosco, Emanuela, Yeung, Jonathan, Pugh, Trevor J., and de Perrot, Marc

Subjects
MESOTHELIOMA, MACROPHAGES, MYELOID cells, TUMOR microenvironment, DELETION mutation
Abstract

Defining the ontogeny of tumor-associated macrophages (TAM) is important to develop therapeutic targets for mesothelioma. We identified two distinct macrophage populations in mouse peritoneal and pleural cavities, the monocyte-derived, small peritoneal/pleural macrophages (SPM), and the tissue-resident large peritoneal/pleural macrophages (LPM). SPM rapidly increased in tumor microenvironment after tumor challenge and contributed to the vast majority of M2-like TAM. The selective depletion of M2-like TAM by conditional deletion of the Dicer1 gene in myeloid cells (D−/−) promoted tumor rejection. Sorted SPM M2-like TAM initiated tumorigenesis in vivo and in vitro, confirming their capacity to support tumor development. The transcriptomic and single-cell RNA sequencing analysis demonstrated that both SPM and LPM contributed to the tumor microenvironment by promoting the IL-2-STAT5 signaling pathway, inflammation, and epithelial–mesenchymal transition. However, while SPM preferentially activated the KRAS and TNF-α/NFkB signaling pathways, LPM activated the IFN-γ response. The importance of LPM in the immune response was confirmed by depleting LPM with intrapleural clodronate liposomes, which abrogated the antitumoral memory immunity. SPM gene signature could be identified in pleural effusion and tumor from patients with untreated mesothelioma. Five genes, TREM2, STAB1, LAIR1, GPNMB, and MARCO, could potentially be specific therapeutic targets. Accordingly, Trem2 gene deletion led to reduced SPM M2-like TAM with compensatory increase in LPM and slower tumor growth. Overall, these experiments demonstrate that SPM M2-like TAM play a key role in mesothelioma development, while LPM more specifically contribute to the immune response. Therefore, selective targeting of monocyte-derived TAM may enhance antitumor immunity through compensatory expansion of tissue-resident TAM. [ABSTRACT FROM AUTHOR]

Published
2023
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