title: A conditional piggyBac transposition system for genetic screening in mice identifies oncogenic networks in pancreatic cancer.
abstract: Here we describe a conditional piggyBac transposition system in mice and report the discovery of large sets of new cancer genes through a pancreatic insertional mutagenesis screen. We identify Foxp1 as an oncogenic transcription factor that drives pancreatic cancer invasion and spread in a mouse model and correlates with lymph node metastasis in human patients with pancreatic cancer. The propensity of piggyBac for open chromatin also enabled genome-wide screening for cancer-relevant noncoding DNA, which pinpointed a Cdkn2a cis-regulatory region. Histologically, we observed different tumor subentities and discovered associated genetic events, including Fign insertions in hepatoid pancreatic cancer. Our studies demonstrate the power of genetic screening to discover cancer drivers that are difficult to identify by other approaches to cancer genome analysis, such as downstream targets of commonly mutated human cancer genes. These piggyBac resources are universally applicable in any tissue context and provide unique experimental access to the genetic complexity of cancer.
authors.affiliation: 1] Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, München, Germany. [2] German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. [3] The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire, UK.
authors.forename: Roland
authors.initials: R
authors.lastname: Rad
authors.affiliation: The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire, UK.
authors.forename: Lena
authors.initials: L
authors.lastname: Rad
authors.affiliation: The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire, UK.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire, UK.
authors.forename: Alexander
authors.initials: A
authors.lastname: Strong
authors.affiliation: The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire, UK.
authors.forename: Hannes
authors.initials: H
authors.lastname: Ponstingl
authors.affiliation: The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire, UK.
authors.forename: Iraad F
authors.initials: IF
authors.lastname: Bronner
authors.affiliation: The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Mayho
authors.affiliation: Department of Pathology, Klinikum Rechts der Isar, Technische Universität München, München, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Steiger
authors.affiliation: 1] Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, München, Germany. [2] German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Weber
authors.affiliation: Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, München, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Hieber
authors.affiliation: Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, München, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Veltkamp
authors.affiliation: Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, München, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Eser
authors.affiliation: 1] Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, München, Germany. [2] German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Geumann
authors.affiliation: Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, München, Germany.
authors.forename: Rupert
authors.initials: R
authors.lastname: Öllinger
authors.affiliation: Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, München, Germany.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Zukowska
authors.affiliation: 1] Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, München, Germany. [2] German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Maxim
authors.initials: M
authors.lastname: Barenboim
authors.affiliation: 1] Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, München, Germany. [2] German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Roman
authors.initials: R
authors.lastname: Maresch
authors.affiliation: Instituto de Medicina Oncológica y Molecular de Asturias (IMOMA), Oviedo, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Cadiñanos
authors.affiliation: The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire, UK.
authors.forename: Mathias
authors.initials: M
authors.lastname: Friedrich
authors.affiliation: Instituto de Biomedicina y Biotecnología de Cantabria (UC-CSIC-SODERCAN), Santander, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Varela
authors.affiliation: Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Fernando
authors.initials: F
authors.lastname: Constantino-Casas
authors.affiliation: Biostatistics and Bioinformatics Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Sarver
authors.affiliation: Bioinformatics and Statistics, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Jelle
authors.initials: J
authors.lastname: Ten Hoeve
authors.affiliation: The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire, UK.
authors.forename: Haydn
authors.initials: H
authors.lastname: Prosser
authors.affiliation: Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, München, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Seidler
authors.affiliation: Institute of Virology, Technische Universität München, Munich, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Bauer
authors.affiliation: Institute of Virology, Technische Universität München, Munich, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwälder
authors.affiliation: The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire, UK.
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Metzakopian
authors.affiliation: Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, München, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Krug
authors.affiliation: Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, München, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Ehmer
authors.affiliation: Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, München, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Schneider
authors.affiliation: Institute of Pathology, Ludwig Maximilians Universität München, München, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Knösel
authors.affiliation: Institute of Pathology, Universität Regensburg, Regensburg, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Rümmele
authors.affiliation: Institute of Pathology, Technische Universität Dresden, Dresden, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Aust
authors.affiliation: Department of Surgery, Technische Universität Dresden, Dresden, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Grützmann
authors.affiliation: Department of Surgery, Technische Universität Dresden, Dresden, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Pilarsky
authors.affiliation: The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire, UK.
authors.forename: Zemin
authors.initials: Z
authors.lastname: Ning
authors.affiliation: Bioinformatics and Statistics, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Lodewyk
authors.initials: L
authors.lastname: Wessels
authors.affiliation: Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, München, Germany.
authors.forename: Roland M
authors.initials: RM
authors.lastname: Schmid
authors.affiliation: The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire, UK.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Quail
authors.affiliation: The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire, UK.
authors.forename: George
authors.initials: G
authors.lastname: Vassiliou
authors.affiliation: Institute of Pathology, Medizinische Universität Insbruck, Insbruck, Austria.
authors.forename: Irene
authors.initials: I
authors.lastname: Esposito
authors.affiliation: The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire, UK.
authors.forename: Pentao
authors.initials: P
authors.lastname: Liu
authors.affiliation: 1] Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, München, Germany. [2] German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Saur
authors.affiliation: The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire, UK.
authors.forename: Allan
authors.initials: A
authors.lastname: Bradley
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004251:DNA Transposable Elements / Q000235:genetics*; D051858:Forkhead Transcription Factors / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D053263:Gene Regulatory Networks; D005813:Genes, Synthetic; D019942:Genes, p16; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009036:Moths / Q000235:genetics; D016254:Mutagenesis, Insertional; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D006180:Proton-Translocating ATPases / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D012097:Repressor Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics; D019076:Transgenes; D019895:Transposases / Q000235:genetics / Q000502:physiology
chemical_list: D004251:DNA Transposable Elements; C486626:FOXP1 protein, human; D051858:Forkhead Transcription Factors; C432917:Foxp1 protein, mouse; C432918:Foxp2 protein, mouse; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D019895:Transposases; D006180:Proton-Translocating ATPases