| A conditional piggyBac transposition system for genetic screening in mice identifies oncogenic networks in pancreatic cancer | | A conditional piggyBac transposition system for genetic screening in mice identifies oncogenic networks in pancreatic cancer | 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 | 2014-12-07T23:00:00Z | <p style="text-align:justify;"><strong class="ms-rteThemeFontFace-1 ms-rteFontSize-2">Abstract</strong></p><p style="text-align:justify;"><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="color:#222222;letter-spacing:0.17000000178813934px;background-color:#ffffff;">Here we describe a conditional </span><em class="ms-rteThemeFontFace-1 ms-rteFontSize-2">piggyBac</em><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="color:#222222;letter-spacing:0.17000000178813934px;background-color:#ffffff;"> 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 </span><em class="ms-rteThemeFontFace-1 ms-rteFontSize-2">piggyBac</em><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="color:#222222;letter-spacing:0.17000000178813934px;background-color:#ffffff;"> for open chromatin also enabled genome-wide screening for cancer-relevant noncoding DNA, which pinpointed a </span><em class="ms-rteThemeFontFace-1 ms-rteFontSize-2">Cdkn2a cis</em><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="color:#222222;letter-spacing:0.17000000178813934px;background-color:#ffffff;">-regulatory region. Histologically, we observed different tumor subentities and discovered associated genetic events, including </span><em class="ms-rteThemeFontFace-1 ms-rteFontSize-2">Fign</em><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="color:#222222;letter-spacing:0.17000000178813934px;background-color:#ffffff;"> 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 </span><em class="ms-rteThemeFontFace-1 ms-rteFontSize-2">piggyBac</em><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="color:#222222;letter-spacing:0.17000000178813934px;background-color:#ffffff;">resources are universally applicable in any tissue context and provide unique experimental access to the genetic complexity of cancer.</span><br></p> | <p><a href="https://www.nature.com/articles/ng.3164">Nature Genet (2015) 47:47-56.</a><br></p> | 198 | | |
