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Mishra, A.* ; Emamgholi, F.* ; Erlangga, Z.* ; Hartleben, B.* ; Unger, K. ; Wolff, K.* ; Teichmann, U.* ; Kessel, M.* ; Woller, N.* ; Kühnel, F.* ; Dow, L.E.* ; Manns, M.P.* ; Vogel, A.* ; Lowe, S.W.* ; Saborowski, A.* ; Saborowski, M.*

Generation of focal mutations and large genomic deletions in the pancreas using inducible in vivo genome editing.

Carcinogenesis 41, 334-344 (2020)
Publ. Version/Full Text Research data DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
Beyond the nearly uniform presence of KRAS mutations, pancreatic cancer is increasingly recognized as a heterogeneous disease. Preclinical in vivo model systems exist, but with the advent of precision oncology, murine models with enhanced genetic flexibility are needed to functionally annotate genetic alterations found in the human malignancy. Here, we describe the generation of focal gene disruptions and large chromosomal deletions via inducible and pancreas-specific expression of Cas9 in adult mice. Experimental mice are derived on demand directly from genetically engineered embryonic stem cells, without the need for further intercrossing. To provide initial validation of our approach, we show that disruption of the E3 ubiquitin ligase Rnf43 accelerates Kras(G12D)-dependent tumourigenesis. Moreover, we demonstrate that this system can be used to rapidly interrogate the impact of complex cancer-associated alleles through the generation of a previously unstudied 1.2 megabase deletion surrounding the CDKN2A and CDKN2B tumour suppressors. Thus, our approach is capable of reproducibly generating biallelic and precise loss of large chromosomal fragments that, in conjunction with mutant Kras, leads to development of pancreatic ductal adenocarcinoma with full penetrance.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Tumor-suppressor Rnf43; Chromosomal Rearrangements; Cancer; Integration; Efficiency; Subtypes; System; Mice; Web
ISSN (print) / ISBN 0143-3334
e-ISSN 1460-2180
Journal Carcinogenesis
Quellenangaben Volume: 41, Issue: 3, Pages: 334-344 Article Number: , Supplement: ,
Publisher Oxford University Press
Publishing Place Great Clarendon St, Oxford Ox2 6dp, England
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Research Unit Radiation Cytogenetics (ZYTO)