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Maresch, R.* ; Müller, S.* ; Veltkamp, C.* ; Öllinger, R.* ; Friedrich, M.* ; Heid, I.M.* ; Steiger, K.* ; Weber, J.* ; Engleitner, T.* ; Barenboim, M.* ; Klein, S.* ; Louzada, S.* ; Banerjee, R.* ; Strong, A.* ; Stauber, T.* ; Gross, N.* ; Geumann, U.* ; Lange, S.* ; Ringelhan, M. ; Varela, I.* ; Unger, K. ; Yang, F.* ; Schmid, R.M.* ; Vassiliou, G.S.* ; Braren, R.* ; Schneider, G.* ; Heikenwälder, M. ; Bradley, A.* ; Saur, D.* ; Rad, R.*

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

Nat. Commun. 7:10770 (2016)
Publ. Version/Full Text Supplement Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords In-vivo; Gene-transfer; Chromosomal Rearrangements; Ductal Adenocarcinoma; Immune-system; Mouse Models; Plasmid Dna; Cell-lines; Stem-cells; Instability
Language english
Publication Year 2016
HGF-reported in Year 2016
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Journal Nature Communications
Quellenangaben Volume: 7, Issue: , Pages: , Article Number: 10770 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed
Institute(s) Institute of Virology (VIRO)
Translational Metabolic Oncology (IDC-TMO)
POF-Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
30203 - Molecular Targets and Therapies
Research field(s) Immune Response and Infection
Radiation Sciences
PSP Element(s) G-551600-001
G-501000-001
PubMed ID 26916719
DOI 10.1038/ncomms10770
WOS ID WOS:000371039900004
Scopus ID 84959295529
Erfassungsdatum 2016-02-28
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