TY - JOUR
T1 - Selective requirement of PI3K/PDK1 signaling for kras oncogene-driven pancreatic cell plasticity and cancer
AU - Eser, Stefan
AU - Reiff, Nina
AU - Messer, Marlena
AU - Seidler, Barbara
AU - Gottschalk, Kathleen
AU - Dobler, Melanie
AU - Hieber, Maren
AU - Arbeiter, Andreas
AU - Klein, Sabine
AU - Kong, Bo
AU - Michalski, Christoph W.
AU - Schlitter, Anna Melissa
AU - Esposito, Irene
AU - Kind, Alexander J.
AU - Rad, Lena
AU - Schnieke, Angelika E.
AU - Baccarini, Manuela
AU - Alessi, Dario R.
AU - Rad, Roland
AU - Schmid, Roland M.
AU - Schneider, Günter
AU - Saur, Dieter
N1 - Funding Information:
We would like to thank Dr. D. Melton, Dr. K. Rajewsky, Dr. N. Bardeesy, Dr. A. Berns, Dr. L. Luo, Dr. D. Tuveson, and Dr. T. Jacks for providing transgenic animals; Dr. P. Vogt for p110α H1047R expression plasmid; and J. Götzfried, V. Klein, T. Schmid, and M. Zukowska for excellent technical assistance. This work was supported by funding from Deutsche Krebshilfe (# 108985 to D.S.), Helmholtz Preclinical Comprehensive Cancer Center (to D.S.), Novartis-Stiftung für therapeutische Forschung (to G.S. and D.S.), and DFG SFB824, TP C9 (to G.S. and D.S.). B.S., G.S., and D.S. designed research; S.E., N.R., M.M., B.S., K.G., M.D., M.H., A.A., S.K., B.K., L.R., R.R., and D.S. performed research; B.K., C.W.M., A.M.S., L.R., I.E., A.J.K., A.E.S., M.B., D.A., R.R., and R.M.S. contributed new reagents/analytic tools; S.E., N.R., M.M., B.S., K.G., M.D., M.H., A.A., A.M.S., I.E., L.R., R.R., and D.S. analyzed data; and B.S., G.S., and D.S. wrote the paper. All authors discussed the results and commented on the manuscript.
PY - 2013/3/18
Y1 - 2013/3/18
N2 - Oncogenic Kras activates a plethora of signaling pathways, but our understanding of critical Ras effectors is still very limited. We show that cell-autonomous phosphoinositide 3-kinase (PI3K) and 3-phosphoinositide-dependent protein kinase 1 (PDK1), but not Craf, are key effectors of oncogenic Kras in the pancreas, mediating cell plasticity, acinar-to-ductal metaplasia (ADM), and pancreatic ductal adenocarcinoma (PDAC) formation. This contrasts with Kras-driven non-small cell lung cancer, where signaling via Craf, but not PDK1, is an essential tumor-initiating event. These in vivo genetic studies together with pharmacologic treatment studies in models of human ADM and PDAC demonstrate tissue-specific differences of oncogenic Kras signaling and define PI3K/PDK1 as a suitable target for therapeutic intervention specifically in PDAC.
AB - Oncogenic Kras activates a plethora of signaling pathways, but our understanding of critical Ras effectors is still very limited. We show that cell-autonomous phosphoinositide 3-kinase (PI3K) and 3-phosphoinositide-dependent protein kinase 1 (PDK1), but not Craf, are key effectors of oncogenic Kras in the pancreas, mediating cell plasticity, acinar-to-ductal metaplasia (ADM), and pancreatic ductal adenocarcinoma (PDAC) formation. This contrasts with Kras-driven non-small cell lung cancer, where signaling via Craf, but not PDK1, is an essential tumor-initiating event. These in vivo genetic studies together with pharmacologic treatment studies in models of human ADM and PDAC demonstrate tissue-specific differences of oncogenic Kras signaling and define PI3K/PDK1 as a suitable target for therapeutic intervention specifically in PDAC.
UR - http://www.scopus.com/inward/record.url?scp=84876437832&partnerID=8YFLogxK
U2 - 10.1016/j.ccr.2013.01.023
DO - 10.1016/j.ccr.2013.01.023
M3 - Article
C2 - 23453624
AN - SCOPUS:84876437832
SN - 1535-6108
VL - 23
SP - 406
EP - 420
JO - Cancer Cell
JF - Cancer Cell
IS - 3
ER -