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 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

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

68 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

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© 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.",

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

Abstract

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