A conditional piggyBac transposition system for genetic screening in mice identifies oncogenic networks in pancreatic cancer

被引：58

作者：

Rad, Roland ^{[1
,2
,3
]}

Rad, Lena ^{[3
]}

Wang, Wei ^{[3
]}

Strong, Alexander ^{[3
]}

Ponstingl, Hannes ^{[3
]}

Bronner, Iraad F. ^{[3
]}

Mayho, Matthew ^{[3
]}

Steiger, Katja ^{[4
]}

Weber, Julia ^{[1
,2
]}

Hieber, Maren ^{[1
]}

Veltkamp, Christian ^{[1
]}

Eser, Stefan ^{[1
]}

Geumann, Ulf ^{[1
,2
]}

Oellinger, Rupert ^{[1
]}

Zukowska, Magdalena ^{[1
]}

Barenboim, Maxim ^{[1
,2
]}

Maresch, Roman ^{[1
,2
]}

Cadinanos, Juan ^{[5
]}

Friedrich, Mathias ^{[3
]}

Varela, Ignacio ^{[6
]}

Constantino-Casas, Fernando ^{[7
]}

Sarver, Aaron ^{[8
]}

ten Hoeve, Jelle ^{[9
]}

Prosser, Haydn ^{[3
]}

Seidler, Barbara ^{[1
]}

Bauer, Judith ^{[10
]}

Heikenwaelder, Mathias ^{[10
]}

Metzakopian, Emmanouil ^{[3
]}

Krug, Anne ^{[1
]}

Ehmer, Ursula ^{[1
]}

Schneider, Guenter ^{[1
]}

Knoesel, Thomas ^{[11
]}

Ruemmele, Petra ^{[12
]}

Aust, Daniela ^{[13
]}

Gruetzmann, Robert ^{[14
]}

Pilarsky, Christian ^{[14
]}

Ning, Zemin ^{[3
]}

Wessels, Lodewyk ^{[9
]}

Schmid, Roland M. ^{[1
]}

Quail, Michael A. ^{[3
]}

Vassiliou, George ^{[3
]}

Esposito, Irene ^{[15
]}

Liu, Pentao

Saur, Dieter ^{[1
,2
]}

Bradley, Allan ^{[3
]}

机构：

[1] Tech Univ Munich, Klinikum Rechts Isar, Dept Med 1, D-80290 Munich, Germany

[2] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany

[3] Wellcome Trust Sanger Inst, Hinxton, Cambs, England

[4] Tech Univ Munich, Klinikum Rechts Isar, Dept Pathol, D-80290 Munich, Germany

[5] IMOMA, Oviedo, Spain

[6] Inst Biomed & Biotecnol Cantabria UC CSIC SODERCA, Santander, Spain

[7] Univ Cambridge, Dept Vet Med, Cambridge, England

[8] Univ Minnesota, Biostat & Bioinformat Mason Canc Ctr, Minneapolis, MN USA

[9] Netherlands Canc Inst, Amsterdam, Netherlands

[10] Tech Univ Munich, Inst Virol, D-80290 Munich, Germany

[11] Univ Munich, Inst Pathol, Munich, Germany

[12] Univ Regensburg, Inst Pathol, D-93053 Regensburg, Germany

[13] Tech Univ Dresden, Inst Pathol, D-01062 Dresden, Germany

[14] Tech Univ Dresden, Dept Surg, D-01062 Dresden, Germany

[15] Med Univ Insbruck, Inst Pathol, Insbruck, Austria

来源：

NATURE GENETICS | 2015年 / 47卷 / 01期

基金：

英国惠康基金;

关键词：

SLEEPING-BEAUTY; CHROMOSOMAL TRANSPOSITION; SOMATIC MUTAGENESIS; EXPRESSION; TOOL; LANDSCAPE; DISCOVERY; PROTEINS; FIDGETIN; PATHWAYS;

D O I：

10.1038/ng.3164

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：47 / +

页数：12

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