title: Polycomb Repressive Complex 2 Is a Barrier to KRAS-Driven Inflammation and Epithelial-Mesenchymal Transition in Non-Small-Cell Lung Cancer.
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 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.
authors.affiliation: Division of Molecular Genetics, Centre for Biomedical Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.
authors.forename: Michela
authors.initials: M
authors.lastname: Serresi
authors.affiliation: Division of Molecular Genetics, Centre for Biomedical Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands. Electronic address: g.gargiulo@nki.nl.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Gargiulo
authors.affiliation: Division of Molecular Genetics, Centre for Biomedical Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.
authors.forename: Natalie
authors.initials: N
authors.lastname: Proost
authors.affiliation: Mouse Clinic Intervention Unit, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.
authors.forename: Bjorn
authors.initials: B
authors.lastname: Siteur
authors.affiliation: The Fels Institute, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Matteo
authors.initials: M
authors.lastname: Cesaroni
authors.affiliation: Division of Molecular Genetics, Centre for Biomedical Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.
authors.forename: Martijn
authors.initials: M
authors.lastname: Koppens
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Hematology/Oncology, Boston Children's Hospital, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Huafeng
authors.initials: H
authors.lastname: Xie
authors.affiliation: Division of Molecular Genetics, Centre for Biomedical Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.
authors.forename: Kate D
authors.initials: KD
authors.lastname: Sutherland
authors.affiliation: Division of Molecular Genetics, Centre for Biomedical Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.
authors.forename: Danielle
authors.initials: D
authors.lastname: Hulsman
authors.affiliation: Division of Molecular Genetics, Centre for Biomedical Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Citterio
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Hematology/Oncology, Boston Children's Hospital, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Stuart
authors.initials: S
authors.lastname: Orkin
authors.affiliation: Division of Molecular Genetics, Centre for Biomedical Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.
authors.forename: Anton
authors.initials: A
authors.lastname: Berns
authors.affiliation: Division of Molecular Genetics, Centre for Biomedical Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Cancer Genomics Centre (CGC.nl), Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands. Electronic address: m.v.lohuizen@nki.nl.
authors.forename: Maarten
authors.initials: M
authors.lastname: van Lohuizen
mesh_terms: D000107:Acetylation; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D004195:Disease Models, Animal; D000071221:Enhancer of Zeste Homolog 2 Protein; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D008822:Mice, Transgenic; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*
chemical_list: D006657:Histones; C117307:KRAS protein, human; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)