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From asbestos-exposure to cancer: a systemic approach to detect loss of homeostatic control in the mesothelial environment

English title From asbestos-exposure to cancer: a systemic approach to detect loss of homeostatic control in the mesothelial environment
Applicant Felley-Bosco Emanuela
Number 147697
Funding scheme Sinergia
Research institution Forschungslabor Molekulare Onkologie Klinik und Poliklinik für Onkologie Universitätsspital Zürich
Institution of higher education University of Zurich - ZH
Main discipline Experimental Cancer Research
Start/End 01.08.2013 - 31.01.2017
Approved amount 1'273'332.00
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All Disciplines (2)

Discipline
Experimental Cancer Research
Pathophysiology

Keywords (9)

inflammation and cancer; cancer immunotolerance; asbestos; YAP signaling; molecular epidemiology; mesothelioma development; hedgehog signaling; calretinin and calcium transduction; developmental pathways and cancer

Lay Summary (French)

Lead
Exposition à l’amiante et développement du cancer : une approche systémique pour détecter la perte d’homéostasie dans l’environnement mésothélial Von der Asbestexposition zur Krebsentstehung : Ein systemischer Ansatz um den Verlust der homöostatischen Kontrolle im mesothelialen Umfeld zu erfassenFrom asbestos-exposure to cancer: a systemic approach to detect loss of homeostatic control in the mesothelial environment
Lay summary

Les maladies associées à une exposition à l’amiante sont encore aujourd’hui un problème majeur de santé publique. Même si l’emploi de l’amiante a été banni dans la plupart des pays occidentaux, y compris en Suisse, l’incidence du mésothéliome continue d’augmenter  à cause de la longue période de latence. Par ailleurs, l’exposition à l’amiante continue dans les pays en voie de développement et des observations expérimentales suggèrent que certains types de fibres artificielles ont les mêmes propriétés que l’amiante, représentant un risque potentiel.
Notre principal objectif est de contribuer à une meilleure compréhension du développement du mésothéliome. Plus précisément, nous souhaitons employer le modèle expérimentale de souris hétérozygotes pour le gène suppresseur des tumeurs Nf2, qui développent un mésothéliome après exposition à l’amiante, dans le but 1) de caractériser le système immunitaire et l’activation de voies de signalisation des cellules souches à des stades précancéreux et cancéreux.  Nous chercherons également  de déterminer 2) si la calrétinine, qui est un marqueur pour ce cancer, joue un rôle dans le développement  du mésothéliome soit par un effet direct dans le tissus mésothélial,  soit par un effet sur l’environnement, y compris le système immunitaire. Nous étudierons aussi 3) les conséquences de variation de GAS5, un ARN-non-codant, dont le gène est supprimé dans le modèle expérimental de mésothéliome.  Finalement, 4) nous confronterons nos résultats expérimentaux  aux données obtenues sur des échantillons cliniques.

Notre travail générera des informations importantes sur les mécanismes de développement du mésothéliome et ces connaissances devraient aussi être utiles pour l’évaluation du risque lors d’exposition à des fibres artificielles.

Direct link to Lay Summary Last update: 16.07.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Putative cancer stem cells may be the key target to inhibit cancer cell repopulation between the intervals of chemoradiation in murine mesothelioma
Wu Licun, Blum Walter, Zhu Chang-Qi, Yun Zhihong, Pecze Laszlo, Kohno Mikihiro, Chan Mei-Lin, Zhao Yidan, Felley-Bosco Emanuela, Schwaller Beat, de Perrot Marc (2018), Putative cancer stem cells may be the key target to inhibit cancer cell repopulation between the intervals of chemoradiation in murine mesothelioma, in BMC Cancer, 18(1), 471-471.
Rscreenorm: normalization of CRISPR and siRNA screen data for more reproducible hit selection
Bachas Costa, Hodzic Jasmina, van der Mijn Johannes C., Stoepker Chantal, Verheul Henk M. W., Wolthuis Rob M. F., Felley-Bosco Emanuela, van Wieringen Wessel N., van Beusechem Victor W., Brakenhoff Ruud H., de Menezes Renée X. (2018), Rscreenorm: normalization of CRISPR and siRNA screen data for more reproducible hit selection, in BMC Bioinformatics, 19(1), 301-301.
Calretinin Functions in Malignant Mesothelioma Cells Cannot Be Replaced by the Closely Related Ca2+-Binding Proteins Calbindin-D28k and Parvalbumin
Wörthmüller Janine, Oberson Anne, Salicio Valérie, Blum Walter, Schwaller Beat (2018), Calretinin Functions in Malignant Mesothelioma Cells Cannot Be Replaced by the Closely Related Ca2+-Binding Proteins Calbindin-D28k and Parvalbumin, in International Journal of Molecular Sciences, 19(12), 4015-4015.
Absence of calretinin protein expression in malignant mesotheliomas from asbestos-exposed NF2+/− mice and mouse mesothelioma cell lines from various mouse strains
Blum Walter, Henzi Thomas, Châtel-Soulet Hugues-Etienne, Pecze Laszlo, Rodriguez Janine Wörthmüller, Vrugt Bart, Schwaller Beat (2018), Absence of calretinin protein expression in malignant mesotheliomas from asbestos-exposed NF2+/− mice and mouse mesothelioma cell lines from various mouse strains, in Biomarker Research, 6(1), 19-19.
Calretinin promotes invasiveness and EMT in malignant mesothelioma cells involving the activation of the FAK signaling pathway
Wörthmüller Janine, Blum Walter, Pecze Laszlo, Salicio Valérie, Schwaller Beat (2018), Calretinin promotes invasiveness and EMT in malignant mesothelioma cells involving the activation of the FAK signaling pathway, in Oncotarget, 9(91), 1-10.
Asbestos: Modern Insights for Toxicology in the Era of Engineered Nanomaterials
Felley-Bosco Emanuela, MacFarlane Marion (2018), Asbestos: Modern Insights for Toxicology in the Era of Engineered Nanomaterials, in Chemical Research in Toxicology, 31(10), 994-1008.
How asbestos drives the tissue towards tumors: YAP activation, macrophage and mesothelial precursor recruitment, RNA editing, and somatic mutations
Rehrauer Hubert, Wu Licun, Blum Walter, Pecze Lazslo, Henzi Thomas, Serre-Beinier Véronique, Aquino Catherine, Vrugt Bart, de Perrot Marc, Schwaller Beat, Felley-Bosco Emanuela (2018), How asbestos drives the tissue towards tumors: YAP activation, macrophage and mesothelial precursor recruitment, RNA editing, and somatic mutations, in Oncogene, 37(20), 2645-2659.
Desthiobiotin-Streptavidin-Affinity Mediated Purification of RNA-Interacting Proteins in Mesothelioma Cells
Kresoja-Rakic Jelena, Felley-Bosco Emanuela (2018), Desthiobiotin-Streptavidin-Affinity Mediated Purification of RNA-Interacting Proteins in Mesothelioma Cells, in Journal of Visualized Experiments, (134), 1-10.
Non-Coding Transcript Heterogeneity in Mesothelioma: Insights from Asbestos-Exposed Mice
Felley-Bosco Emanuela, Rehrauer Hubert (2018), Non-Coding Transcript Heterogeneity in Mesothelioma: Insights from Asbestos-Exposed Mice, in International Journal of Molecular Sciences, 19(4), 1163-1163.
ZHAW Waedenswil: A new Approach in the Fight against Cancer
Rimann Markus (2018), ZHAW Waedenswil: A new Approach in the Fight against Cancer, in CHIMIA International Journal for Chemistry, 72(3), 166-168.
Live-Cell Mesothelioma Biobank to Explore Mechanisms of Tumor Progression
Oehl Kathrin, Kresoja-Rakic Jelena, Opitz Isabelle, Vrugt Bart, Weder Walter, Stahel Rolf, Wild Peter, Felley-Bosco Emanuela (2018), Live-Cell Mesothelioma Biobank to Explore Mechanisms of Tumor Progression, in Frontiers in Oncology, 8, 1-10.
Erratum to: Establishment of immortalized murine mesothelial cells and a novel mesothelioma cell line
Blum Walter, Pecze László, Felley-Bosco Emanuela, Worthmüller-Rodriguez Janine, Wu Licun, Vrugt Bart, de Perrot Marc, Schwaller Beat (2017), Erratum to: Establishment of immortalized murine mesothelial cells and a novel mesothelioma cell line, in In Vitro Cellular & Developmental Biology - Animal, 53(9), 853-853.
The “don't eat me” signal CD47 is a novel diagnostic biomarker and potential therapeutic target for diffuse malignant mesothelioma
Schürch Christian M., Forster Stefan, Brühl Frido, Yang Sara H., Felley-Bosco Emanuela, Hewer Ekkehard (2017), The “don't eat me” signal CD47 is a novel diagnostic biomarker and potential therapeutic target for diffuse malignant mesothelioma, in OncoImmunology, 7(1), e1373235-e1373235.
A Novel BRCA1-Associated Protein-1 Isoform Affects Response of Mesothelioma Cells to Drugs Impairing BRCA1-Mediated DNA Repair
Parrotta Rossella, Okonska Agata, Ronner Manuel, Weder Walter, Stahel Rolf, Penengo Lorenza, Felley-Bosco Emanuela (2017), A Novel BRCA1-Associated Protein-1 Isoform Affects Response of Mesothelioma Cells to Drugs Impairing BRCA1-Mediated DNA Repair, in Journal of Thoracic Oncology, 12(8), 1309-1319.
Posttranscriptional Regulation Controls Calretinin Expression in Malignant Pleural Mesothelioma
Kresoja-Rakic Jelena, Sulemani Merve, Kirschner Michaela B., Ronner Manuel, Reid Glen, Kao Steven, Schwaller Beat, Weder Walter, Stahel Rolf A., Felley-Bosco Emanuela (2017), Posttranscriptional Regulation Controls Calretinin Expression in Malignant Pleural Mesothelioma, in Frontiers in Genetics, 8, 1-10.
Stem Cell Factor-Based Identification and Functional Properties of In Vitro-Selected Subpopulations of Malignant Mesothelioma Cells
Blum Walter, Pecze László, Felley-Bosco Emanuela, Wu Licun, de Perrot Marc, Schwaller Beat (2017), Stem Cell Factor-Based Identification and Functional Properties of In Vitro-Selected Subpopulations of Malignant Mesothelioma Cells, in Stem Cell Reports, 8(4), 1005-1017.
Patient-Derived Xenograft Establishment from Human Malignant Pleural Mesothelioma
Wu Licun, Allo Ghassan, John Thomas, Li Ming, Tagawa Tetsuzo, Opitz Isabelle, Anraku Masaki, Yun Zhihong, Pintilie Melania, Pitcher Bethany, Liu Geoffrey, Feld Ron, Johnston Michael R., de Perrot Marc, Tsao Ming-Sound (2017), Patient-Derived Xenograft Establishment from Human Malignant Pleural Mesothelioma, in Clinical Cancer Research, 23(4), 1060-1067.
Stem cell factors-based identification and functional properties of in vitro-selected subpopulations of malignant mesothelioma cells
Blum Walter, Pecze Laszlo, Felley-Bosco Emanuela, Wu Licun, de Perrot Marc, Schwaller Beat (2017), Stem cell factors-based identification and functional properties of in vitro-selected subpopulations of malignant mesothelioma cells, in Stem Cell Reports.
Antagonizing the Hedgehog Pathway with Vismodegib Impairs Malignant Pleural Mesothelioma Growth In Vivo by Affecting Stroma.
Meerang Mayura, Bérard Karima, Felley-Bosco Emanuela, Lauk Olivia, Vrugt Bart, Boss Andreas, Kenkel David, Broggini-Tenzer Angela, Stahel Rolf A, Arni Stephan, Weder Walter, Opitz Isabelle (2016), Antagonizing the Hedgehog Pathway with Vismodegib Impairs Malignant Pleural Mesothelioma Growth In Vivo by Affecting Stroma., in Molecular cancer therapeutics, 15(5), 1095-105.
Identification of cis- and trans-acting elements regulating calretinin expression in mesothelioma cells
Kresoja-Rakic Jelena, Kapaklikaya Esra, Ziltener Gabriela, Dalcher Damian, Santoro Raffaella, Christensen Brock C, Johnson Kevin C, Schwaller Beat, Weder Walter, Stahel Rolf, Felley-Bosco Emanuela (2016), Identification of cis- and trans-acting elements regulating calretinin expression in mesothelioma cells, in Oncotarget, 7, 21272.
Kinesin family members KIF11 and KIF23 as potential therapeutic targets in malignant pleural mesothelioma
Kato Tatsuya, Lee Daiyoon, Wu Licun, Patel Priya, Young Ahn, Wada Hironobu, Hu Hsin-Pei, Ujiie Hideki, Kaji Mitsuhito, Kano Satoshi, Matsuge Shinichi, Domen Hiromitsu, Kaga Kichizo, Matsui Yoshiro, Kanno Hiromi, Hatanaka Yutaka, Hatanaka Kanako, Matsuno Yoshihiro, de Perrot Marc, Yasufuku Kazuhiro (2016), Kinesin family members KIF11 and KIF23 as potential therapeutic targets in malignant pleural mesothelioma, in International Journal of Oncology, 448-456.
Low Merlin expression and high Survivin labeling index are indicators for poor prognosis in patients with malignant pleural mesothelioma
Meerang Mayura, B{é}}rard Karima, Friess Martina, Bitanihirwe Byron K.Y., Soltermann Alex, Vrugt Bart, Felley-Bosco Emanuela, Bueno Raphael, Richards William G., Seifert Burkhardt, Stahel Rolf, Weder Walter, Opitz Isabelle (2016), Low Merlin expression and high Survivin labeling index are indicators for poor prognosis in patients with malignant pleural mesothelioma, in Molecular Oncology, 10(8), 1255-1265.
SORORIN and PLK1 as potential therapeutic targets in malignant pleural mesothelioma
Kato Tatsuya, Lee Daiyoon, Wu Licun, Patel Priya, Young Ahn, Wada Hironobu, Hu Hsin-Pei, Ujiie Hideki, Kaji Mitsuhito, Kano Satoshi, Matsuge Shinichi, Domen Hiromitsu, Kanno Hiromi, Hatanaka Yutaka, Hatanaka Kanako, Kaga Kichizo, Matsui Yoshiro, Matsuno Yoshihiro, De Perrot Marc, Yasufuku Kazuhiro (2016), SORORIN and PLK1 as potential therapeutic targets in malignant pleural mesothelioma, in International Journal of Oncology, 2411-2420.
Establishment of immortalized murine mesothelial cells and a novel mesothelioma cell line
Blum Walter, Pecze László, Felley-Bosco Emanuela, Worthmüller-Rodriguez Janine, Wu Licun, Vrugt Bart, de Perrot Marc, Schwaller Beat (2015), Establishment of immortalized murine mesothelial cells and a novel mesothelioma cell line, in In Vitro Cellular & Developmental Biology - Animal, 51(7), 714-721.
Autophagy correlates with the therapeutic responsiveness of Malignant pleural mesothelioma in 3D models
Barbone D., Follo C., Echeverry N., Gerbaudo V.H., Klabatsa A., Bueno R., Felley-Bosco E., Broaddus V.C. (2015), Autophagy correlates with the therapeutic responsiveness of Malignant pleural mesothelioma in 3D models, in PLoS ONE, 10(8), 1180-1194.
Hedgehog Signaling in Malignant Pleural Mesothelioma.
Felley-Bosco Emanuela, Opitz Isabelle, Meerang Mayura (2015), Hedgehog Signaling in Malignant Pleural Mesothelioma., in Genes, 6(3), 500-11.
Inhibition of autophagy sensitizes malignant pleural mesothelioma cells to dual PI3K/mTOR inhibitors.
Echeverry N, Ziltener G, Barbone D, Weder W, Stahel R A, Broaddus V C, Felley-Bosco E (2015), Inhibition of autophagy sensitizes malignant pleural mesothelioma cells to dual PI3K/mTOR inhibitors., in Cell death & disease, 6, e1757-1757.
Overexpression or absence of calretinin in mouse primary mesothelial cells inversely affects proliferation and cell migration
Blum Walter, Pecze Laszlo, Felley-Bosco Emanuela, Schwaller Beat (2015), Overexpression or absence of calretinin in mouse primary mesothelial cells inversely affects proliferation and cell migration, in RESPIRATORY RESEARCH, 16, 1-16.
Prevalence of BRCA-1 associated protein 1 germline mutation in sporadic malignant pleural mesothelioma cases.
Rusch Andreas, Ziltener Gabriela, Nackaerts Kristiaan, Weder Walter, Stahel Rolf A, Felley-Bosco Emanuela (2015), Prevalence of BRCA-1 associated protein 1 germline mutation in sporadic malignant pleural mesothelioma cases., in Lung cancer (Amsterdam, Netherlands), 87(1), 77-9.
Routes of Ca2+ shuttling during Ca2+ oscillations: Focus on the role of mitochondrial Ca2+ handling and cytosolic Ca2+ buffers
Pecze László, Blum Walter, Schwaller Beat (2015), Routes of Ca2+ shuttling during Ca2+ oscillations: Focus on the role of mitochondrial Ca2+ handling and cytosolic Ca2+ buffers, in Journal of Biological Chemistry, 290(47), 28214-28230.
Searching for targets for the systemic therapy of mesothelioma.
Stahel R A, Weder W, Felley-Bosco E, Petrausch U, Curioni-Fontecedro A, Schmitt-Opitz I, Peters S (2015), Searching for targets for the systemic therapy of mesothelioma., in Annals of oncology : official journal of the European Society for Medical Oncology / ESMO, 26(8), 1649-60.
GAS5 long non-coding RNA in malignant pleural mesothelioma.
Renganathan Arun, Kresoja-Rakic Jelena, Echeverry Nohemy, Ziltener Gabriela, Vrugt Bart, Opitz Isabelle, Stahel Rolf A, Felley-Bosco Emanuela (2014), GAS5 long non-coding RNA in malignant pleural mesothelioma., in Molecular cancer, 13, 119-119.
Hippo/YAP pathway for targeted therapy.
Felley-Bosco Emanuela, Stahel Rolf (2014), Hippo/YAP pathway for targeted therapy., in Translational lung cancer research, 3(2), 75-83.

Collaboration

Group / person Country
Types of collaboration
Prof. Isabelle Opitz/Zürich University Hospital Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. H. Rehrauer/Zurich University/ETHZ Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Laszlo Forro, EPFL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. B. Vrugt/Institute of Surgical Pathology/Zurich University Hospital Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. V. Serre-Beinier/ University of Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events



Self-organised

Title Date Place
Mini-symposium on mesothelioma research 28.10.2016 Toronto, Canada
Mini-symposium on mesothelioma research 16.01.2015 Zürich, Switzerland

Communication with the public

Communication Title Media Place Year
Other activities Laboratory open day German-speaking Switzerland 2015

Awards

Title Year
Early Postdoc.Mobility 2017

Associated projects

Number Title Start Funding scheme
139226 IncuCyte-based high throughput imaging-based platform for determination of cellular and molecular events in real time in cultured cells in vitro: application to nanomaterial studies, cancer and cardiovascular research 01.12.2011 R'EQUIP
133657 Malignant Pleural Mesothelioma - an integral approach for better outcome 01.07.2011 SNSF Professorships
182690 RNA editing in mesothelioma: a new therapeutic target? 01.10.2018 Project funding (Div. I-III)
147234 Clinical Validation of a Multiplexed Peptide-based Serum Signature for Malignant Pleural Mesothelioma using Selected Reaction Monitoring 01.03.2013 Fellowships for prospective researchers
130680 Knock-out mice for the calcium-binding proteins parvalbumin, calbindin D-28k and calretinin. Models for muscle and brain diseases. 01.05.2010 Project funding (Div. I-III)
155952 Parvalbumin deficiency - a common endpoint mouse model for Autism Spectrum Disorders? 01.01.2015 Project funding (Div. I-III)

Abstract

Malignant pleural mesothelioma (MPM) is a cancer most often associated with the exposure to asbestos fibers. Although asbestos has been banned in most Western countries the incidence of MPM is still raising and asbestos-related diseases are still a major public health problem. In addition MPM incidence will also rise in countries, where asbestos has not been banned yet and where there are no stringent health protection policies. Of concern, mesothelioma could also be induced by man-made fibers (e.g. nanomaterials). Therefore, the investigation of molecular mechanisms of asbestos-induced carcinogenesis in a systemic approach should provide tools for molecular epidemiology in fiber-exposed individuals and will contribute to the understanding of inflammation-driven carcinogenesis. Our working hypothesis is that chronic inflammation/injury activates stem cell signalling and continuous stimulation of repair in an inflammatory setting leads to oncogenic events and escape from immune control. The work proposed herein involves three teams with a long-standing experience in mesothelioma research. Each team has a specific profile with respect to MPM research and the plan is to contribute to this project according to each team’s expertise. All teams will use the same experimental model, i.e. mice heterozygous for the tumor suppressor Nf2 (NF2+/-), which develop mesothelioma after exposure to asbestos, with the aim to characterize immune system and stem cell signalling activation in precancerous stages and during carcinogenesis. In addition we will functionally address the question, whether calretinin, which is currently considered as a positive marker for the identification of MPM, has a role in mesothelioma development. Besides the common work on the identical experimental animal model, each of the three groups will investigate specific molecular aspects in in vitro and in vivo models and results will be confirmed with observations obtained in clinical MPM samples. Our specific aims are to:•- acquire knowledge about the kinetics of the evolution of mesothelium environment and mesothelium tissue during asbestos-driven tumorigenesis•- evaluate the role of calretinin in MPM tumorigenesis including effects on immunotolerance and investigate protein molecular domains of calretinin and pathways possibly responsible for MPM formation•- explore the significance of variation in GAS5, a non-coding RNA, which is decreased upon asbestos-induced tumorigenesis Results obtained within this proposal are expected to provide clinically relevant information on mesothelioma tumorigenesis mechanisms, and the knowledge acquired could also be useful for future molecular epidemiology risk assessments on manmade materials.
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