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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

Otras publicaciones de la misma revista o congreso con autores/as de la Universidad de Cantabria

 Fuente: Nat Med. 2014 Nov;20(11):1340-7

 Año de publicación: 2014

Nº de páginas: 8

Tipo de publicación: Artículo de Revista

 DOI: 10.1038/nm.3646

ISSN: 1078-8956,1546-170X

Autores/as

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

BANERGEE, RUBY

YAN, FANGTANG

LEE, CHANG-LUNG

MODING, EVERETT J

KIRSCH, DAVID G

SCHEIDELER, ANGELIKA

ALESSI, DARIO R

BRADLEY, ALLAN

KIND, ALEXANDER

SCHNIEKE, ANGELIKA E

RODEWALD, HANS REIMER

RAD, ROLAND

SCHMID, ROLAND M

SCHNEIDER, GÜNTER

SAUR, DIETER