Polycomb Repressive Complex 2 Is a Barrier to KRAS-Driven Inflammation and Epithelial-Mesenchymal Transition in Non-Small-Cell Lung Cancer

Michela Serresi; Gaetano Gargiulo; Natalie Proost; Bjorn Siteur; Matteo Cesaroni; Martijn Koppens; Huafeng Xie; Kate D Sutherland; Danielle Hulsman; Elisabetta Citterio; Stuart Orkin; Anton Berns; Maarten van Lohuizen

Journal article

Polycomb Repressive Complex 2 Is a Barrier to KRAS-Driven Inflammation and Epithelial-Mesenchymal Transition in Non-Small-Cell Lung Cancer

Michela Serresi, Gaetano Gargiulo, Natalie Proost, Bjorn Siteur, Matteo Cesaroni, Martijn Koppens, Huafeng Xie, Kate D Sutherland, Danielle Hulsman, Elisabetta Citterio, Stuart Orkin, Anton Berns, Maarten van Lohuizen

CANCER CELL | CELL PRESS | Published : 2016

DOI: 10.1016/j.ccell.2015.12.006

Abstract

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 phenotyp..

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University of Melbourne Researchers

Kate Sutherland Author Medical Biology (w.e.h.i.)

Grants

Awarded by Dutch Cancer Society (KWF)

Funding Acknowledgements

We are grateful to M. Melis for Luminex experiments and I. de Rink for help with sequencing data. We thank J.-Y. Song for pathology; E. Tanger, M. Cozijnsen, and NKI Genomics Core, Microscopy, FACS, and Animal Pathology and Animal Facilities for technical assistance; and C. Creasy (GSK) for the GSK126 compound. We also thank F. Scheeren and E. Guccione, for critically reading the manuscript, M. Ogrunc and A. Gruszka for manuscript proofreading, and A. Sparmann for advice. This work was supported by grants from the European Union Marie Curie Actions (G.G.), the Fondazione Lorini (G.G.), the Dutch Cancer Society (KWF; NKI 2013-61093 and NKI 2014-7208; G.G. and M.v.L.) and the Netherlands Organization for Scientific Research (NWO) to Cancer Genomics Netherlands (CGC.nl; M.v.L.). This work is dedicated to the memory of M.S.'s father, Luigi Serresi.