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

• Published in: Nature medicine Vol. 20; no. 11; pp. 1340 - 1347
• Main Authors: Schönhuber, Nina, Seidler, Barbara, Schuck, Kathleen, Veltkamp, Christian, Schachtler, Christina, Zukowska, Magdalena, Eser, Stefan, Feyerabend, Thorsten B, Paul, Mariel C, Eser, Philipp, Klein, Sabine, Lowy, Andrew M, Banerjee, Ruby, Yang, Fangtang, Lee, Chang-Lung, Moding, Everett J, Kirsch, David G, Scheideler, Angelika, Alessi, Dario R, Varela, Ignacio, Bradley, Allan, Kind, Alexander, Schnieke, Angelika E, Rodewald, Hans-Reimer, Rad, Roland, Schmid, Roland M, Schneider, Günter, Saur, Dieter
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2014; Nature Publishing Group
• Subjects: 13; 13/95; 14/19; 14/35; 38; 38/39; 42/70; 45; 59; 631/67; 631/67/70; 64; 64/60; 82; 96; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Analysis; Animals; Biomedicine; Cancer Research; Carcinogenesis; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Care and treatment; Cell Lineage; Development and progression; Female; Gene expression; Gene targeting; Gene therapy; Genetic aspects; Genetic engineering; Genetic Engineering - methods; Genetic recombination; Green Fluorescent Proteins - metabolism; Health aspects; Inactivation; Infectious Diseases; Male; Mast Cells - metabolism; Mast Cells - pathology; Metabolic Diseases; Mice; Models, Biological; Molecular Medicine; Molecular Targeted Therapy; Neoplasm Metastasis; Neurosciences; Oncogenes; Pancreas - pathology; Pancreatic cancer; Precancerous Conditions - metabolism; Precancerous Conditions - pathology; Precision Medicine - methods; Proto-Oncogene Proteins p21(ras) - metabolism; Recombinases; Recombinases - metabolism; Reproducibility of Results; Species Specificity; Stem cells; Stromal Cells - metabolism; Stromal Cells - pathology; Subpopulations; Tamoxifen; technical-report; Testing; Time Factors; Tumors; Germany
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.3646

The next generation of genetically engineered mouse models of pancreatic cancer involving a new inducible dual-recombinase system that combines Flp- FRT and Cre- loxP . 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.