Eed is a context-dependent tumor-suppressor gene in KRAS-driven lung cancer
•
PRC2 is a barrier to KRAS-driven inflammation and EMT in NSCLC
•
Kras, Eed, and Trp53 loss promote formation of an aggressive mucinous adenocarcinoma
•
Eed loss promotes a chromatin switch at developmental and pro-oncogenic loci
Summary
Polycomb repressive complexes (PRC) are frequently implicated in human cancer, acting either as oncogenes or tumor suppressors. Here, we show that PRC2 is a critical regulator of KRAS-driven non-small cell lung cancer progression. Modulation of PRC2 by either Ezh2 overexpression or Eed deletion enhances KRAS-driven adenomagenesis and inflammation, respectively. Eed-loss-driven inflammation leads to massive macrophage recruitment and marked decline in tissue function. Additional Trp53 inactivation activates a cell-autonomous epithelial-to-mesenchymal transition program leading to an invasive mucinous adenocarcinoma. A switch between methylated/acetylated chromatin underlies the tumor phenotypic evolution, prominently involving genes controlled by Hippo/Wnt signaling. Our observations in the mouse models were conserved in human cells. Importantly, PRC2 inactivation results in context-dependent phenotypic alterations, with implications for its therapeutic application.
Present address: Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia and Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia
