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Cancer tolerance to chromosomal instability is driven by Stat1 inactivation in vivo

View ORCID ProfileMichael Schubert, Christy Hong, Laura J. Jilderda, Marta Requesens Rueda, Andréa E. Tijhuis, Judith E. Simon, Petra L. Bakker, Jon L. Cooper, Aristi Damaskou, René Wardenaar, Bjorn Bakker, Sahil Gupta, Anouk van den Brink, Lorena Andrade Ruiz, Miriam H. Koster, Sameh A. Youssef, Danielle Luinenburg, Alex Strong, Thomas Engleitner, Hannes Ponstingl, Gerald de Haan, Alain de Bruin, Roland Rad, Hans W. Nijman, René H. Medema, Marcel A.T.M. van Vugt, Marco de Bruyn, Diana C.J. Spierings, Maria Colomé-Tatché, George S. Vassiliou, View ORCID ProfileFloris Foijer
doi: https://doi.org/10.1101/2021.12.03.471107
Michael Schubert
1European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, 9713 AV, Groningen, the Netherlands
2Division of Cell Biology and Cancer Genomics Center, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands
3Institute of Computational Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
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  • ORCID record for Michael Schubert
  • For correspondence: m.schubert@rug.nl f.foijer@umcg.nl
Christy Hong
1European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, 9713 AV, Groningen, the Netherlands
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Laura J. Jilderda
1European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, 9713 AV, Groningen, the Netherlands
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Marta Requesens Rueda
1European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, 9713 AV, Groningen, the Netherlands
4Department of Obstetrics and Gynaecology, University of Groningen, University Medical Center Groningen, 9713 AV, Groningen, the Netherlands
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Andréa E. Tijhuis
1European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, 9713 AV, Groningen, the Netherlands
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Judith E. Simon
1European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, 9713 AV, Groningen, the Netherlands
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Petra L. Bakker
1European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, 9713 AV, Groningen, the Netherlands
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Jon L. Cooper
5Wellcome–Medical Research Council (MRC) Cambridge Stem Cell Institute, Cambridge, United Kingdom
6Department of Haematology, Cambridge University Hospitals National Health Service (NHS) Trust, Cambridge, United Kingdom
7Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom
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Aristi Damaskou
5Wellcome–Medical Research Council (MRC) Cambridge Stem Cell Institute, Cambridge, United Kingdom
6Department of Haematology, Cambridge University Hospitals National Health Service (NHS) Trust, Cambridge, United Kingdom
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René Wardenaar
1European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, 9713 AV, Groningen, the Netherlands
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Bjorn Bakker
1European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, 9713 AV, Groningen, the Netherlands
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Sahil Gupta
1European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, 9713 AV, Groningen, the Netherlands
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Anouk van den Brink
1European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, 9713 AV, Groningen, the Netherlands
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Lorena Andrade Ruiz
1European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, 9713 AV, Groningen, the Netherlands
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Miriam H. Koster
8Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 AV, Groningen, the Netherlands
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Sameh A. Youssef
9Dutch Molecular Pathology Center, Department of Biomolecular Health Sciences, Utrecht University, Faculty of Veterinary Medicine, 3584 CL, Utrecht, the Netherlands
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Danielle Luinenburg
1European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, 9713 AV, Groningen, the Netherlands
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Alex Strong
7Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom
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Thomas Engleitner
10Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technische Universität München, 81675, Munich, Germany
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Hannes Ponstingl
7Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom
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Gerald de Haan
1European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, 9713 AV, Groningen, the Netherlands
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Alain de Bruin
8Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 AV, Groningen, the Netherlands
9Dutch Molecular Pathology Center, Department of Biomolecular Health Sciences, Utrecht University, Faculty of Veterinary Medicine, 3584 CL, Utrecht, the Netherlands
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Roland Rad
10Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technische Universität München, 81675, Munich, Germany
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Hans W. Nijman
4Department of Obstetrics and Gynaecology, University of Groningen, University Medical Center Groningen, 9713 AV, Groningen, the Netherlands
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René H. Medema
2Division of Cell Biology and Cancer Genomics Center, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands
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Marcel A.T.M. van Vugt
11Department of Medical Oncology, University of Groningen, University Medical Center Groningen, 9713 AV, Groningen, the Netherlands
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Marco de Bruyn
4Department of Obstetrics and Gynaecology, University of Groningen, University Medical Center Groningen, 9713 AV, Groningen, the Netherlands
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Diana C.J. Spierings
1European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, 9713 AV, Groningen, the Netherlands
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Maria Colomé-Tatché
3Institute of Computational Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
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George S. Vassiliou
5Wellcome–Medical Research Council (MRC) Cambridge Stem Cell Institute, Cambridge, United Kingdom
6Department of Haematology, Cambridge University Hospitals National Health Service (NHS) Trust, Cambridge, United Kingdom
7Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom
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Floris Foijer
1European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, 9713 AV, Groningen, the Netherlands
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  • ORCID record for Floris Foijer
  • For correspondence: m.schubert@rug.nl f.foijer@umcg.nl
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Abstract

Chromosomal instability is a hallmark of cancer, but also an instigator of aneuploidy-induced stress, reducing cellular fitness. To better understand how cells with CIN adjust to aneuploidy and adopt a malignant fate in vivo, we performed a genome-wide mutagenesis screen in mice. We find that specifically aneuploid tumors inactivate Stat1 signaling in combination with increased Myc activity. By contrast, loss of p53 is common, but not enriched in CIN tumors. Validation in another tissue type confirmed that CIN promotes immune cell infiltration, which is alleviated by Stat1 loss combined with Myc activation, but not with p53 inactivation, or Myc activation alone. Importantly, we find that this mechanism is preserved in human aneuploid cancers. We conclude that aneuploid cancers inactivate Stat1 signaling to circumvent immune surveillance.

Competing Interest Statement

M.A.T.M.v.V. has acted on the Scientific Advisory Board of Repare Therapeutics, which is unrelated to this work. The other authors declare no conflict of interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Cancer tolerance to chromosomal instability is driven by Stat1 inactivation in vivo
Michael Schubert, Christy Hong, Laura J. Jilderda, Marta Requesens Rueda, Andréa E. Tijhuis, Judith E. Simon, Petra L. Bakker, Jon L. Cooper, Aristi Damaskou, René Wardenaar, Bjorn Bakker, Sahil Gupta, Anouk van den Brink, Lorena Andrade Ruiz, Miriam H. Koster, Sameh A. Youssef, Danielle Luinenburg, Alex Strong, Thomas Engleitner, Hannes Ponstingl, Gerald de Haan, Alain de Bruin, Roland Rad, Hans W. Nijman, René H. Medema, Marcel A.T.M. van Vugt, Marco de Bruyn, Diana C.J. Spierings, Maria Colomé-Tatché, George S. Vassiliou, Floris Foijer
bioRxiv 2021.12.03.471107; doi: https://doi.org/10.1101/2021.12.03.471107
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Cancer tolerance to chromosomal instability is driven by Stat1 inactivation in vivo
Michael Schubert, Christy Hong, Laura J. Jilderda, Marta Requesens Rueda, Andréa E. Tijhuis, Judith E. Simon, Petra L. Bakker, Jon L. Cooper, Aristi Damaskou, René Wardenaar, Bjorn Bakker, Sahil Gupta, Anouk van den Brink, Lorena Andrade Ruiz, Miriam H. Koster, Sameh A. Youssef, Danielle Luinenburg, Alex Strong, Thomas Engleitner, Hannes Ponstingl, Gerald de Haan, Alain de Bruin, Roland Rad, Hans W. Nijman, René H. Medema, Marcel A.T.M. van Vugt, Marco de Bruyn, Diana C.J. Spierings, Maria Colomé-Tatché, George S. Vassiliou, Floris Foijer
bioRxiv 2021.12.03.471107; doi: https://doi.org/10.1101/2021.12.03.471107

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