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: 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
• Journal: Nature genetics (Nat Genet) Vol. 47 Issue 1 Pg. 47-56 (Jan 2015) ISSN: 1546-1718 [Electronic] United States
• PMID: 25485836 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA Transposable Elements
• FOXP1 protein, human
• Forkhead Transcription Factors
• Foxp1 protein, mouse
• Foxp2 protein, mouse
• Neoplasm Proteins
• RNA, Small Interfering
• Repressor Proteins
• Transposases
• Proton-Translocating ATPases

Topics

• Amino Acid Sequence
• Animals
• Cell Transformation, Neoplastic (genetics)
• DNA Transposable Elements (genetics)
• Forkhead Transcription Factors (analysis, antagonists & inhibitors, genetics)
• Gene Expression Profiling
• Gene Expression Regulation
• Gene Knock-In Techniques
• Gene Regulatory Networks
• Genes, Synthetic
• Genes, p16
• Humans
• Mice
• Mice, Transgenic
• Molecular Sequence Data
• Moths (genetics)
• Mutagenesis, Insertional
• Neoplasm Proteins (antagonists & inhibitors, genetics)
• Pancreatic Neoplasms (chemistry, genetics, pathology)
• Proton-Translocating ATPases (genetics)
• RNA, Small Interfering (pharmacology)
• Repressor Proteins (analysis, antagonists & inhibitors, genetics)
• Transgenes
• Transposases (genetics, physiology)