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

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

doi:10.1038/nm.3646

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

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 VarelaAllan Bradley, Alexander Kind, Angelika E Schnieke, Hans-Reimer Rodewald, Roland Rad, Roland M. Schmid, Günter Schneider, Dieter Saur (Lead / Corresponding author)

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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.

Original language	English
Pages (from-to)	1340-1347
Number of pages	8
Journal	Nature Medicine
Volume	20
Issue number	11
Early online date	19 Oct 2014
DOIs	https://doi.org/10.1038/nm.3646
Publication status	Published - Nov 2014

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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., ... Saur, D. (2014). A next-generation dual-recombinase system for time- and host-specific targeting of pancreatic cancer. Nature Medicine, 20(11), 1340-1347. https://doi.org/10.1038/nm.3646

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

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.",

author = "Nina Sch{\"o}nhuber and Barbara Seidler and Kathleen Schuck and Christian Veltkamp and Christina Schachtler and Magdalena Zukowska and Stefan Eser and Feyerabend, {Thorsten B.} and Paul, {Mariel C.} and Philipp Eser and Sabine Klein and Lowy, {Andrew M.} and Ruby Banerjee and Fangtang Yang and Chang-Lung Lee and Moding, {Everett J.} and Kirsch, {David G.} and Angelika Scheideler and Alessi, {Dario R.} and Ignacio Varela and Allan Bradley and Alexander Kind and Schnieke, {Angelika E} and Hans-Reimer Rodewald and Roland Rad and Schmid, {Roland M.} and G{\"u}nter Schneider and Dieter Saur",

year = "2014",

month = nov,

doi = "10.1038/nm.3646",

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Schönhuber, N, Seidler, B, Schuck, K, Veltkamp, C, Schachtler, C, Zukowska, M, Eser, S, Feyerabend, TB, Paul, MC, Eser, P, Klein, S, Lowy, AM, Banerjee, R, Yang, F, Lee, C-L, Moding, EJ, Kirsch, DG, Scheideler, A, Alessi, DR, Varela, I, Bradley, A, Kind, A, Schnieke, AE, Rodewald, H-R, Rad, R, Schmid, RM, Schneider, G & Saur, D 2014, 'A next-generation dual-recombinase system for time- and host-specific targeting of pancreatic cancer', Nature Medicine, vol. 20, no. 11, pp. 1340-1347. https://doi.org/10.1038/nm.3646

TY - JOUR

T1 - A next-generation dual-recombinase system for time- and host-specific targeting of pancreatic cancer

AU - Schönhuber, Nina

AU - Seidler, Barbara

AU - Schuck, Kathleen

AU - Veltkamp, Christian

AU - Schachtler, Christina

AU - Zukowska, Magdalena

AU - Eser, Stefan

AU - Feyerabend, Thorsten B.

AU - Paul, Mariel C.

AU - Eser, Philipp

AU - Klein, Sabine

AU - Lowy, Andrew M.

AU - Banerjee, Ruby

AU - Yang, Fangtang

AU - Lee, Chang-Lung

AU - Moding, Everett J.

AU - Kirsch, David G.

AU - Scheideler, Angelika

AU - Alessi, Dario R.

AU - Varela, Ignacio

AU - Bradley, Allan

AU - Kind, Alexander

AU - Schnieke, Angelika E

AU - Rodewald, Hans-Reimer

AU - Rad, Roland

AU - Schmid, Roland M.

AU - Schneider, Günter

AU - Saur, Dieter

PY - 2014/11

Y1 - 2014/11

N2 - 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.

AB - 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.

U2 - 10.1038/nm.3646

DO - 10.1038/nm.3646

M3 - Article

C2 - 25326799

SN - 1078-8956

VL - 20

SP - 1340

EP - 1347

JO - Nature Medicine

JF - Nature Medicine

IS - 11

ER -

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

Abstract

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