Nina Schönhuber, Barbara Seidler, Kathleen Schuck, Christian Veltkamp, Christina Schachtler, Magdalena Zukowska, Stefan Eser, Thorsten B. Feyerabend, Mariel C. Paul, Philipp Eser, Sabine Klein, Andrew M. Lowy, Ruby Banerjee, Fangtang Yang, Chang-Lung Lee, Everett J. Moding, David G. Kirsch, Angelika Scheideler, Dario R. Alessi, Ignacio Varela, Allan Bradley, Alexander Kind, Angelika E. Schnieke, Hans-Reimer Rodewald, Roland Rad, Roland M. Schmid, Günter Schneider & Dieter Saur. (31-10-2014).

Nature America, 2014, doi:10.1038/nm.3646

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Department: 

Research Area C

Abstract: 

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.