English
 
User Manual Privacy Policy Disclaimer Contact us
  Advanced SearchBrowse

Item

ITEM ACTIONSEXPORT

Released

Journal Article

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

MPS-Authors
/persons/resource/persons15917

Teichmann,  U.
Department of Molecular Cell Biology, MPI for biophysical chemistry, Max Planck Society;

/persons/resource/persons15322

Kessel,  M.
Research Group of Developmental Biology, MPI for biophysical chemistry, Max Planck Society;

External Ressource
No external resources are shared
Fulltext (public)
There are no public fulltexts stored in PuRe
Supplementary Material (public)
There is no public supplementary material available
Citation

Mishra, A., Emamgholi, F., Erlangga, Z., Hartleben, B., Unger, K., Wolff, K., et al. (2019). Generation of focal mutations and large genomic deletions in the pancreas using inducible in vivo genome editing. Carcinogenesis, (in press). doi:10.1093/carcin/bgz108.


Cite as: http://hdl.handle.net/21.11116/0000-0003-CBB8-9
Abstract
Beyond the nearly uniform presence of KRAS mutations, pancreatic cancer is increasingly recognized as a heterogeneous disease. Pre-clinical 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 KrasG12D-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 CKDN2A 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.