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

Roland Rad; Lena Rad; Wei Wang; Alexander Strong; Hannes Ponstingl; Iraad F. Bronner; Matthew Mayho; Katja Steiger; Julia Weber; Maren Hieber; Christian Veltkamp; Stefan Eser; Ulf Geumann; Rupert Öllinger; Magdalena Zukowska; Maxim Barenboim; Roman Maresch; Juan Cadiñanos; Mathias Friedrich; Ignacio Varela; Fernando Constantino-Casas; Aaron Sarver; Jelle Ten Hoeve; Haydn Prosser; Barbara Seidler; Judith Bauer; Mathias Heikenwälder; Emmanouil Metzakopian; Anne Krug; Ursula Ehmer; Günter Schneider; Thomas Knösel; Petra Rümmele; Daniela Aust; Robert Grützmann; Christian Pilarsky; Zemin Ning; Lodewyk Wessels; Roland M. Schmid; Michael A. Quail; George Vassiliou; Irene Esposito; Pentao Liu; Dieter Saur; Allan Bradley

doi:10.1038/ng.3164

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

Roland Rad, Lena Rad, Wei Wang, Alexander Strong, Hannes Ponstingl, Iraad F. Bronner, Matthew Mayho, Katja Steiger, Julia Weber, Maren Hieber, Christian Veltkamp, Stefan Eser, Ulf Geumann, Rupert Öllinger, Magdalena Zukowska, Maxim Barenboim, Roman Maresch, Juan Cadiñanos, Mathias Friedrich, Ignacio VarelaFernando Constantino-Casas, Aaron Sarver, Jelle Ten Hoeve, Haydn Prosser, Barbara Seidler, Judith Bauer, Mathias Heikenwälder, Emmanouil Metzakopian, Anne Krug, Ursula Ehmer, Günter Schneider, Thomas Knösel, Petra Rümmele, Daniela Aust, Robert Grützmann, Christian Pilarsky, Zemin Ning, Lodewyk Wessels, Roland M. Schmid, Michael A. Quail, George Vassiliou, Irene Esposito, Pentao Liu, Dieter Saur, Allan Bradley

Masonic Cancer Center

Research output: Contribution to journal › Article › peer-review

63 Scopus citations

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.

Original language	English (US)
Pages (from-to)	47-56
Number of pages	10
Journal	Nature Genetics
Volume	47
Issue number	1
DOIs	https://doi.org/10.1038/ng.3164
State	Published - Jan 2015

Bibliographical note

Funding Information:
We thank the Wellcome Trust Sanger Institute Research Support Facility for excellent technical assistance as well as K. Yusa and B. Göttgens for discussions and advice. The work was supported by the Wellcome Trust (to A.B.), the German Cancer Consortium (to R.R.) and the Helmholtz Gemeinschaft (PCCC Consortium; to R.R. and D.S.).

Publisher Copyright:
© 2015 Nature America, Inc. All rights reserved.

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Rad, R., Rad, L., Wang, W., Strong, A., Ponstingl, H., Bronner, I. F., Mayho, M., Steiger, K., Weber, J., Hieber, M., Veltkamp, C., Eser, S., Geumann, U., Öllinger, R., Zukowska, M., Barenboim, M., Maresch, R., Cadiñanos, J., Friedrich, M., ... Bradley, A. (2015). A conditional piggyBac transposition system for genetic screening in mice identifies oncogenic networks in pancreatic cancer. Nature Genetics, 47(1), 47-56. https://doi.org/10.1038/ng.3164

Rad, R, Rad, L, Wang, W, Strong, A, Ponstingl, H, Bronner, IF, Mayho, M, Steiger, K, Weber, J, Hieber, M, Veltkamp, C, Eser, S, Geumann, U, Öllinger, R, Zukowska, M, Barenboim, M, Maresch, R, Cadiñanos, J, Friedrich, M, Varela, I, Constantino-Casas, F, Sarver, A, Ten Hoeve, J, Prosser, H, Seidler, B, Bauer, J, Heikenwälder, M, Metzakopian, E, Krug, A, Ehmer, U, Schneider, G, Knösel, T, Rümmele, P, Aust, D, Grützmann, R, Pilarsky, C, Ning, Z, Wessels, L, Schmid, RM, Quail, MA, Vassiliou, G, Esposito, I, Liu, P, Saur, D & Bradley, A 2015, 'A conditional piggyBac transposition system for genetic screening in mice identifies oncogenic networks in pancreatic cancer', Nature Genetics, vol. 47, no. 1, pp. 47-56. https://doi.org/10.1038/ng.3164

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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.",

author = "Roland Rad and Lena Rad and Wei Wang and Alexander Strong and Hannes Ponstingl and Bronner, {Iraad F.} and Matthew Mayho and Katja Steiger and Julia Weber and Maren Hieber and Christian Veltkamp and Stefan Eser and Ulf Geumann and Rupert {\"O}llinger and Magdalena Zukowska and Maxim Barenboim and Roman Maresch and Juan Cadi{\~n}anos and Mathias Friedrich and Ignacio Varela and Fernando Constantino-Casas and Aaron Sarver and {Ten Hoeve}, Jelle and Haydn Prosser and Barbara Seidler and Judith Bauer and Mathias Heikenw{\"a}lder and Emmanouil Metzakopian and Anne Krug and Ursula Ehmer and G{\"u}nter Schneider and Thomas Kn{\"o}sel and Petra R{\"u}mmele and Daniela Aust and Robert Gr{\"u}tzmann and Christian Pilarsky and Zemin Ning and Lodewyk Wessels and Schmid, {Roland M.} and Quail, {Michael A.} and George Vassiliou and Irene Esposito and Pentao Liu and Dieter Saur and Allan Bradley",

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

Abstract

Bibliographical note

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