Multiplexed pancreatic genome engineering and cancer induction by transfection-based CRISPR/Cas9 delivery in mice

Roman Maresch, Sebastian Mueller, Christian Veltkamp, Rupert Öllinger, Mathias Friedrich, Irina Heid, Katja Steiger, Julia Weber, Thomas Engleitner, Maxim Barenboim, Sabine Klein, Sandra Louzada, Ruby Banerjee, Alexander Strong, Teresa Stauber, Nina Gross, Ulf Geumann, Sebastian Lange, Marc Ringelhan, Ignacio Varela, Kristian Unger, Fengtang Yang, Roland M. Schmid, George S. Vassiliou, Rickmer Braren, Günter Schneider, Mathias Heikenwalder, Allan Bradley, Dieter Saur and Roland Rad ()
Additional contact information
Roman Maresch: Klinikum rechts der Isar, Technische Universität München
Sebastian Mueller: Klinikum rechts der Isar, Technische Universität München
Christian Veltkamp: Klinikum rechts der Isar, Technische Universität München
Rupert Öllinger: Klinikum rechts der Isar, Technische Universität München
Mathias Friedrich: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Irina Heid: Institute of Radiology, Klinikum rechts der Isar, Technischen Universität München
Katja Steiger: Klinikum rechts der Isar, Technische Universität München
Julia Weber: Klinikum rechts der Isar, Technische Universität München
Thomas Engleitner: Klinikum rechts der Isar, Technische Universität München
Maxim Barenboim: Klinikum rechts der Isar, Technische Universität München
Sabine Klein: Klinikum rechts der Isar, Technische Universität München
Sandra Louzada: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Ruby Banerjee: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Alexander Strong: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Teresa Stauber: Klinikum rechts der Isar, Technische Universität München
Nina Gross: Klinikum rechts der Isar, Technische Universität München
Ulf Geumann: Klinikum rechts der Isar, Technische Universität München
Sebastian Lange: Klinikum rechts der Isar, Technische Universität München
Marc Ringelhan: Klinikum rechts der Isar, Technische Universität München
Ignacio Varela: Instituto de Biomedicina y Biotecnología de Cantabria
Kristian Unger: Helmholtz Zentrum München, Research Unit Radiation Cytogenetics
Fengtang Yang: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Roland M. Schmid: Klinikum rechts der Isar, Technische Universität München
George S. Vassiliou: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Rickmer Braren: Institute of Radiology, Klinikum rechts der Isar, Technischen Universität München
Günter Schneider: Klinikum rechts der Isar, Technische Universität München
Mathias Heikenwalder: Institute of Virology, Technische Universität München/Helmholtz Zentrum München
Allan Bradley: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Dieter Saur: Klinikum rechts der Isar, Technische Universität München
Roland Rad: Klinikum rechts der Isar, Technische Universität München

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: 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.

Date: 2016
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/ncomms10770 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10770

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms10770

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().