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dc.contributor.authorMaresch, Roman
dc.contributor.authorMueller, Sebastian
dc.contributor.authorVeltkamp, Christian
dc.contributor.authorÖllinger, Rupert
dc.contributor.authorFriedrich, Mathias
dc.contributor.authorHeid, Irina
dc.contributor.authorSteiger, Katja
dc.contributor.authorWeber, Julia
dc.contributor.authorEngleitner, Thomas
dc.contributor.authorBarenboim, Maxim
dc.contributor.authorKlein, Sabine
dc.contributor.authorLouzada, Sandra
dc.contributor.authorBanerjee, Ruby
dc.contributor.authorStrong, Alexander
dc.contributor.authorStauber, Teresa
dc.contributor.authorGross, Nina
dc.contributor.authorGeumann, Ulf
dc.contributor.authorLange, Sebastian
dc.contributor.authorRingelhan, Marc
dc.contributor.authorVarela, Ignacio
dc.contributor.authorUnger, Kristian
dc.contributor.authorYang, Fengtang
dc.contributor.authorSchmid, Roland M
dc.contributor.authorVassiliou, George S
dc.contributor.authorBraren, Rickmer
dc.contributor.authorSchneider, Günter
dc.contributor.authorHeikenwalder, Mathias
dc.contributor.authorBradley, Allan
dc.contributor.authorSaur, Dieter
dc.contributor.authorRad, Roland
dc.date.accessioned2020-10-14T23:30:17Z
dc.date.available2020-10-14T23:30:17Z
dc.date.issued2016-02-26
dc.identifier.issn2041-1723
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/311495
dc.description.abstractMouse 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.
dc.format.mediumElectronic
dc.languageeng
dc.publisherSpringer Science and Business Media LLC
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectPancreas
dc.subjectAnimals
dc.subjectMice
dc.subjectPancreatic Neoplasms
dc.subjectNeoplasms, Experimental
dc.subjectChromosome Deletion
dc.subjectTranslocation, Genetic
dc.subjectBRCA2 Protein
dc.subjectMagnetic Resonance Imaging
dc.subjectElectroporation
dc.subjectImmunohistochemistry
dc.subjectTransfection
dc.subjectGenetic Engineering
dc.subjectPolymerase Chain Reaction
dc.subjectSequence Analysis, DNA
dc.subjectPhylogeny
dc.subjectMutation
dc.subjectGenome
dc.subjectProto-Oncogene Proteins p21(ras)
dc.subjectHigh-Throughput Nucleotide Sequencing
dc.subjectCarcinogenesis
dc.subjectCRISPR-Cas Systems
dc.titleMultiplexed pancreatic genome engineering and cancer induction by transfection-based CRISPR/Cas9 delivery in mice.
dc.typeArticle
prism.publicationDate2016
prism.publicationNameNat Commun
prism.startingPage10770
prism.volume7
dc.identifier.doi10.17863/CAM.58588
dcterms.dateAccepted2016-01-19
rioxxterms.versionofrecord10.1038/ncomms10770
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2016-02-26
dc.contributor.orcidVassiliou, George [0000-0003-4337-8022]
dc.contributor.orcidBradley, Allan [0000-0002-2349-8839]
dc.identifier.eissn2041-1723
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMedical Research Council (MC_PC_12009)
cam.issuedOnline2016-02-26


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International