Abstract IA05: Polycomb repressive complex-2 is a barrier to Kras-driven inflammation and epithelial-mesenchymal transition in non-small cell lung cancer

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 (NSCLC) 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 (EMT) 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. Citation Format: Michela Serresi, Gaetano Gargiulo, Nathalie Proost, Bjorn Siteur, Matteo Cesaroni, Martijn Koppens, Huafeng Xie, Kate Sutherland, Danielle Hulsman, Elisabetta Citterio, Stuart Orkin, Anton Berns, Maarten van Lohuizen. Polycomb repressive complex-2 is a barrier to Kras-driven inflammation and epithelial-mesenchymal transition in non-small cell lung cancer. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr IA05.