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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Acknowledgements

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.).

Author information

Author notes

    • Roland Rad
    •  & Lena Rad

    These authors contributed equally to this work.

Affiliations

  1. Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, München, Germany.

    • Roland Rad
    • , Julia Weber
    • , Maren Hieber
    • , Christian Veltkamp
    • , Stefan Eser
    • , Ulf Geumann
    • , Rupert Öllinger
    • , Magdalena Zukowska
    • , Maxim Barenboim
    • , Roman Maresch
    • , Barbara Seidler
    • , Anne Krug
    • , Ursula Ehmer
    • , Günter Schneider
    • , Roland M Schmid
    •  & Dieter Saur
  2. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Roland Rad
    • , Julia Weber
    • , Ulf Geumann
    • , Maxim Barenboim
    • , Roman Maresch
    •  & Dieter Saur
  3. The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire, UK.

    • Roland Rad
    • , Lena Rad
    • , Wei Wang
    • , Alexander Strong
    • , Hannes Ponstingl
    • , Iraad F Bronner
    • , Matthew Mayho
    • , Mathias Friedrich
    • , Haydn Prosser
    • , Emmanouil Metzakopian
    • , Zemin Ning
    • , Michael A Quail
    • , George Vassiliou
    • , Pentao Liu
    •  & Allan Bradley
  4. Department of Pathology, Klinikum Rechts der Isar, Technische Universität München, München, Germany.

    • Katja Steiger
  5. Instituto de Medicina Oncológica y Molecular de Asturias (IMOMA), Oviedo, Spain.

    • Juan Cadiñanos
  6. Instituto de Biomedicina y Biotecnología de Cantabria (UC-CSIC-SODERCAN), Santander, Spain.

    • Ignacio Varela
  7. Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.

    • Fernando Constantino-Casas
  8. Biostatistics and Bioinformatics Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA.

    • Aaron Sarver
  9. Bioinformatics and Statistics, The Netherlands Cancer Institute, Amsterdam, the Netherlands.

    • Jelle ten Hoeve
    •  & Lodewyk Wessels
  10. Institute of Virology, Technische Universität München, Munich, Germany.

    • Judith Bauer
    •  & Mathias Heikenwälder
  11. Institute of Pathology, Ludwig Maximilians Universität München, München, Germany.

    • Thomas Knösel
  12. Institute of Pathology, Universität Regensburg, Regensburg, Germany.

    • Petra Rümmele
  13. Institute of Pathology, Technische Universität Dresden, Dresden, Germany.

    • Daniela Aust
  14. Department of Surgery, Technische Universität Dresden, Dresden, Germany.

    • Robert Grützmann
    •  & Christian Pilarsky
  15. Institute of Pathology, Medizinische Universität Insbruck, Insbruck, Austria.

    • Irene Esposito

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Contributions

R.R. and A.B. designed the study. R.R. wrote the paper. R.R., L.R., W.W., A. Strong, H. Ponstingl, I.F.B., M.M., K.S., J.W., M. Hieber, C.V., S.E., U.G., R.Ö., M.Z., M.B., R.M., J.C., M.F., I.V., F.C.-C., A. Sarver, B.S., J.B., E.M., A.K., U.E., M.A.Q., G.V., I.E. and D.S. performed experiments or bioinformatics or histological analyses. J.t.H., H. Prosser, M. Heikenwälder, G.S., T.K., P.R., D.A., R.G., C.P., Z.N., L.W., R.M.S., M.A.Q., P.L. and D.S. contributed biological or analytical tools.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Roland Rad.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–22 and Supplementary Table 3

Excel files

  1. 1.

    Supplementary Table 1

    Tapdance analysis to identify common insertion sites in 49 pancreatic cancers.

  2. 2.

    Supplementary Table 2

    GCK (Gaussian Kernel Convolution) analysis to identify common insertion sites in 49 pancreatic cancers.

About this article

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DOI

https://doi.org/10.1038/ng.3164

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