Maresch, Roman; Mueller, Sebastian; Veltkamp, Christian; Öllinger, Rupert; Friedrich, Mathias; Heid, Irina; Steiger, Katja; Weber, Julia; Engleitner, Thomas; Barenboim, Maxim; Klein, Sabine; Louzada, Sandra; Banerjee, Ruby; Strong, Alexander; Stauber, Teresa; Gross, Nina; Geumann, Ulf; Lange, Sebastian; Ringelhan, Marc; Varela, Ignacio; Unger, Kristian; Yang, Fengtang; Schmid, Roland M.; Vassiliou, George S.; Braren, Rickmer; Schneider, Günter; Heikenwalder, Mathias; Bradley, Allan; Saur, Dieter; Rad, Roland (2016): Multiplexed pancreatic genome engineering and cancer induction by transfection-based CRISPR/Cas9 delivery in mice. In: Nature Communications, Vol. 7, 10770 |
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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.
Item Type: | Journal article |
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Faculties: | Medicine |
Subjects: | 600 Technology > 610 Medicine and health |
URN: | urn:nbn:de:bvb:19-epub-38108-6 |
ISSN: | 2041-1723 |
Language: | English |
ID Code: | 38108 |
Deposited On: | 04. May 2017 13:11 |
Last Modified: | 04. Nov 2020 14:45 |
- BASE
- Maresch, Roman
- Mueller, Sebastian
- Veltkamp, Christian
- Öllinger, Rupert
- Friedrich, Mathias
- Heid, Irina
- Steiger, Katja
- Weber, Julia
- Engleitner, Thomas
- Barenboim, Maxim
- Klein, Sabine
- Louzada, Sandra
- Banerjee, Ruby
- Strong, Alexander
- Stauber, Teresa
- Gross, Nina
- Geumann, Ulf
- Lange, Sebastian
- Ringelhan, Marc
- Varela, Ignacio
- Unger, Kristian
- Yang, Fengtang
- Schmid, Roland M.
- Vassiliou, George S.
- Braren, Rickmer
- Schneider, Günter
- Heikenwalder, Mathias
- Bradley, Allan
- Saur, Dieter
- Rad, Roland
- Google Scholar
- Maresch, Roman
- Mueller, Sebastian
- Veltkamp, Christian
- Öllinger, Rupert
- Friedrich, Mathias
- Heid, Irina
- Steiger, Katja
- Weber, Julia
- Engleitner, Thomas
- Barenboim, Maxim
- Klein, Sabine
- Louzada, Sandra
- Banerjee, Ruby
- Strong, Alexander
- Stauber, Teresa
- Gross, Nina
- Geumann, Ulf
- Lange, Sebastian
- Ringelhan, Marc
- Varela, Ignacio
- Unger, Kristian
- Yang, Fengtang
- Schmid, Roland M.
- Vassiliou, George S.
- Braren, Rickmer
- Schneider, Günter
- Heikenwalder, Mathias
- Bradley, Allan
- Saur, Dieter
- Rad, Roland