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Schönhuber, N.* ; Seidler, B.* ; Schuck, K.* ; Veltkamp, C.* ; Schachtler, C.* ; Zukowska, M.* ; Eser, S.* ; Feyerabend, T.B.* ; Paul, M.C.* ; Eser, P.* ; Klein, S.* ; Lowy, A.M.* ; Banerjee, R.* ; Yang, F.* ; Lee, C.L.* ; Moding, E.J.* ; Kirsch, D.G.* ; Scheideler, A. ; Alessi, D.R.* ; Varela, I.* ; Bradley, A.* ; Kind, A.* ; Schnieke, A.E.* ; Rodewald, H.R.* ; Rad, R.* ; Schmid, R.M.* ; Schneider, G.* ; Saur, D.*

A next-generation dual-recombinase system for time- and host-specific targeting of pancreatic cancer.

Nat. Med. 20, 1340-1347 (2014)
Publ. Version/Full Text DOI
Open Access Green as soon as Postprint is submitted to ZB.
Genetically engineered mouse models (GEMMs) have dramatically improved our understanding of tumor evolution and therapeutic resistance. However, sequential genetic manipulation of gene expression and targeting of the host is almost impossible using conventional Cre-loxP-based models. We have developed an inducible dual-recombinase system by combining flippase-FRT (Flp-FRT) and Cre-loxP recombination technologies to improve GEMMs of pancreatic cancer. This enables investigation of multistep carcinogenesis, genetic manipulation of tumor subpopulations (such as cancer stem cells), selective targeting of the tumor microenvironment and genetic validation of therapeutic targets in autochthonous tumors on a genome-wide scale. As a proof of concept, we performed tumor cell-autonomous and nonautonomous targeting, recapitulated hallmarks of human multistep carcinogenesis, validated genetic therapy by 3-phosphoinositide-dependent protein kinase inactivation as well as cancer cell depletion and show that mast cells in the tumor microenvironment, which had been thought to be key oncogenic players, are dispensable for tumor formation.
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Publication type Article: Journal article
Document type Scientific Article
ISSN (print) / ISBN 1078-8956
e-ISSN 1546-170X
Journal Nature medicine
Quellenangaben Volume: 20, Issue: 11, Pages: 1340-1347 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place New York, NY
Reviewing status Peer reviewed