Selective Requirement of PI3K/PDK1 Signaling for Kras Oncogene-Driven Pancreatic Cell Plasticity and Cancer

Stefan Eser; Nina Reiff; Marlena Messer; Barbara Seidler; Kathleen Gottschalk; Melanie Dobler; Maren Hieber; Andreas Arbeiter; Sabine Klein; Bo Kong; Christoph W. Michalski; Anna Melissa Schlitter; Irene Esposito; Alexander J. Kind; Lena Rad; Angelika E. Schnieke; Manuela Baccarini; Dario R. Alessi; Roland Rad; Roland M. Schmid; Guenter Schneider; Dieter Saur

doi:10.1016/j.ccr.2013.01.023

Selective Requirement of PI3K/PDK1 Signaling for Kras Oncogene-Driven Pancreatic Cell Plasticity and Cancer

Stefan Eser, Nina Reiff, Marlena Messer, Barbara Seidler, Kathleen Gottschalk, Melanie Dobler, Maren Hieber, Andreas Arbeiter, Sabine Klein, Bo Kong, Christoph W. Michalski, Anna Melissa Schlitter, Irene Esposito, Alexander J. Kind, Lena Rad, Angelika E. Schnieke, Manuela Baccarini, Dario R. Alessi, Roland Rad, Roland M. SchmidGuenter Schneider, Dieter Saur

Research output: Contribution to journal › Article › peer-review

286 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	406-420
Number of pages	15
Journal	Cancer Cell
Volume	23
Issue number	3
DOIs	https://doi.org/10.1016/j.ccr.2013.01.023
Publication status	Published - 2013

Keywords

RAS ONCOGENE
TUMOR-SUPPRESSOR
MICE
DUCTAL ADENOCARCINOMA
PI3K
C-RAF
IN-VIVO
EGF RECEPTOR
TUMORIGENESIS
MOUSE MODEL

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccr.2013.01.023

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Eser, S., Reiff, N., Messer, M., Seidler, B., Gottschalk, K., Dobler, M., Hieber, M., Arbeiter, A., Klein, S., Kong, B., Michalski, C. W., Schlitter, A. M., Esposito, I., Kind, A. J., Rad, L., Schnieke, A. E., Baccarini, M., Alessi, D. R., Rad, R., ... Saur, D. (2013). Selective Requirement of PI3K/PDK1 Signaling for Kras Oncogene-Driven Pancreatic Cell Plasticity and Cancer. Cancer Cell, 23(3), 406-420. https://doi.org/10.1016/j.ccr.2013.01.023

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title = "Selective Requirement of PI3K/PDK1 Signaling for Kras Oncogene-Driven Pancreatic Cell Plasticity and Cancer",

abstract = "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.",

keywords = "RAS ONCOGENE, TUMOR-SUPPRESSOR, MICE, DUCTAL ADENOCARCINOMA, PI3K, C-RAF, IN-VIVO, EGF RECEPTOR, TUMORIGENESIS, MOUSE MODEL",

author = "Stefan Eser and Nina Reiff and Marlena Messer and Barbara Seidler and Kathleen Gottschalk and Melanie Dobler and Maren Hieber and Andreas Arbeiter and Sabine Klein and Bo Kong and Michalski, {Christoph W.} and Schlitter, {Anna Melissa} and Irene Esposito and Kind, {Alexander J.} and Lena Rad and Schnieke, {Angelika E.} and Manuela Baccarini and Alessi, {Dario R.} and Roland Rad and Schmid, {Roland M.} and Guenter Schneider and Dieter Saur",

year = "2013",

doi = "10.1016/j.ccr.2013.01.023",

language = "English",

volume = "23",

pages = "406--420",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "3",

}

Eser, S, Reiff, N, Messer, M, Seidler, B, Gottschalk, K, Dobler, M, Hieber, M, Arbeiter, A, Klein, S, Kong, B, Michalski, CW, Schlitter, AM, Esposito, I, Kind, AJ, Rad, L, Schnieke, AE, Baccarini, M, Alessi, DR, Rad, R, Schmid, RM, Schneider, G & Saur, D 2013, 'Selective Requirement of PI3K/PDK1 Signaling for Kras Oncogene-Driven Pancreatic Cell Plasticity and Cancer', Cancer Cell, vol. 23, no. 3, pp. 406-420. https://doi.org/10.1016/j.ccr.2013.01.023

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, Guenter

AU - Saur, Dieter

PY - 2013

Y1 - 2013

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.

KW - RAS ONCOGENE

KW - TUMOR-SUPPRESSOR

KW - MICE

KW - DUCTAL ADENOCARCINOMA

KW - PI3K

KW - C-RAF

KW - IN-VIVO

KW - EGF RECEPTOR

KW - TUMORIGENESIS

KW - MOUSE MODEL

U2 - 10.1016/j.ccr.2013.01.023

DO - 10.1016/j.ccr.2013.01.023

M3 - Article

SN - 1535-6108

VL - 23

SP - 406

EP - 420

JO - Cancer Cell

JF - Cancer Cell

IS - 3

ER -

Selective Requirement of PI3K/PDK1 Signaling for Kras Oncogene-Driven Pancreatic Cell Plasticity and Cancer

Abstract

Keywords

UN SDGs

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