@article{10902/10989,
year = {2016},
month = {2},
url = {http://hdl.handle.net/10902/10989},
abstract = {Mouse transgenesis has provided fundamental insights into pancreatic cancer, but is limited by the long duration of allele/model generation. Here we show transfection-based multiplexed delivery of CRISPR/Cas9 to the pancreas of adult mice, allowing simultaneous editing of multiple gene sets in individual cells. We use the method to induce pancreatic cancer and exploit CRISPR/Cas9 mutational signatures for phylogenetic tracking of metastatic disease. Our results demonstrate that CRISPR/Cas9-multiplexing enables key applications, such as combinatorial gene-network analysis, in vivo synthetic lethality screening and chromosome engineering. Negative-selection screening in the pancreas using multiplexed-CRISPR/Cas9 confirms the vulnerability of pancreatic cells to Brca2-inactivation in a Kras-mutant context. We also demonstrate modelling of chromosomal deletions and targeted somatic engineering of inter-chromosomal translocations, offering multifaceted opportunities to study complex structural variation, a hallmark of pancreatic cancer. The low-frequency mosaic pattern of transfection-based CRISPR/Cas9 delivery faithfully recapitulates the stochastic nature of human tumorigenesis, supporting wide applicability for biological/preclinical research.},
publisher = {Nature Publishing Group},
publisher = {Nature Communications 7, Article number: 10770 (2016)},
title = {Multiplexed pancreatic genome engineering and cancer induction by transfection-based CRISPR/Cas9 delivery in mice},
author = {Maresch, Roman and Mueller, Sebastian and Veltkamp, Christian and Ollinger, Rupert and Friedrich, Mathias and Heid, Irina and Steiger, Katja and Weber, Julia and Engleitner, Thomas and Barenboim, Maxim and Klein, Sabine and Louzada, Sandra and Banerjee, Ruby and Strong, Alexander and Stauber, Teresa and Gross, Nina and Geumann, Ulf and Lange, Sebastian and Ringelhan, Marc and Varela Egocheaga, Ignacio},
}