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

Schubert, M.; Hong, C.; Jilderda, L. J.; Requesens-Rueda, M.; Tijhuis, A. E.; Simon, J. E.; Bakker, P. L.; Cooper, J.; Damaskou, A.; Wardenaar, R.; Bakker, B.; Gupta, S.; van den Brink, A.; Andrade-Ruiz, L.; Koster, M. H.; Youssef, S. A.; Luinenburg, D.; Strong, A.; Engleiter, T.; Ponstingl, H.; de Haan, G.; de Bruin, A.; Rad, R.; Nijman, H. W.; Medema, R. H.; van Vugt, M.; de Bruyn, M.; Spierings, D. C. J.; Colome-Thatche, M.; Vassiliou, G.; Foijer, F.

doi:10.1101/2021.12.03.471107

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bioRxiv · 10.1101/2021.12.03.471107

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

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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.

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Schubert, M., Hong, C., Jilderda, L. J., Requesens-Rueda, M., Tijhuis, A. E., Simon, J. E., Bakker, P. L., Cooper, J., Damaskou, A., Wardenaar, R., Bakker, B., Gupta, S., van den Brink, A., Andrade-Ruiz, L., Koster, M. H., Youssef, S. A., Luinenburg, D., Strong, A., Engleiter, T., Ponstingl, H., de Haan, G., de Bruin, A., Rad, R., Nijman, H. W., Medema, R. H., van Vugt, M., de Bruyn, M., Spierings, D. C. J., Colome-Thatche, M., Vassiliou, G., Foijer, F.. 2021-12-04. Cancer tolerance to chromosomal instability is driven by Stat1 inactivation in vivo. https://doi.org/10.1101/2021.12.03.471107

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