Cancer tolerance to chromosomal instability is driven by Stat1 inactivation \textitin vivo
Authors: Schubert, Michael and Hong, Christy and Jilderda, Laura J. and Rueda, Marta Requesens and Tijhuis, Andréa E. and Simon, Judith E. and Bakker, Petra L. and Cooper, Jon L. and Damaskou, Aristi and Wardenaar, René and Bakker, Bjorn and Gupta, Sahil and van den Brink, Anouk and Ruiz, Lorena Andrade and Koster, Miriam H. and Youssef, Sameh A. and Luinenburg, Danielle and Strong, Alex and Engleitner, Thomas and Ponstingl, Hannes and de Haan, Gerald and de Bruin, Alain and Rad, Roland and Nijman, Hans W. and Medema, René H. and van Vugt, Marcel A.T.M. and de Bruyn, Marco and Spierings, Diana C.J. and Colomé-Tatché, Maria and Vassiliou, George S. and Foijer, Floris Year: 2021
Abstract
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.
Notes
Extracted Concepts
- Aneuploid cancers inactivate Stat1 to circumvent immune surveillance
- Aneuploid tumors inactivate Stat1 signaling with increased Myc activity
- Chromosomal instability promotes immune cell infiltration into tumors
- Stat1 inactivation mechanism is conserved between mouse and human aneuploid cancers
- Stat1 loss combined with Myc activation alleviates CIN-induced immune infiltration
- p53 loss is common but not enriched in chromosomally unstable tumors