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 & 2 others Guenter Schneider, Dieter Saur

    Research output: Contribution to journalArticle

    159 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 languageEnglish
    Pages (from-to)406-420
    Number of pages15
    JournalCancer Cell
    Volume23
    Issue number3
    DOIs
    Publication statusPublished - 2013

    Keywords

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

    Cite this

    Eser, S., Reiff, N., Messer, M., Seidler, B., Gottschalk, K., Dobler, M., ... 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
    Eser, Stefan ; Reiff, Nina ; Messer, Marlena ; Seidler, Barbara ; Gottschalk, Kathleen ; Dobler, Melanie ; Hieber, Maren ; Arbeiter, Andreas ; Klein, Sabine ; Kong, Bo ; Michalski, Christoph W. ; Schlitter, Anna Melissa ; Esposito, Irene ; Kind, Alexander J. ; Rad, Lena ; Schnieke, Angelika E. ; Baccarini, Manuela ; Alessi, Dario R. ; Rad, Roland ; Schmid, Roland M. ; Schneider, Guenter ; Saur, Dieter. / Selective Requirement of PI3K/PDK1 Signaling for Kras Oncogene-Driven Pancreatic Cell Plasticity and Cancer. In: Cancer Cell. 2013 ; Vol. 23, No. 3. pp. 406-420.
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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.",
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    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",
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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, 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

    Selective Requirement of PI3K/PDK1 Signaling for Kras Oncogene-Driven Pancreatic Cell Plasticity and Cancer. / Eser, Stefan; Reiff, Nina; Messer, Marlena; Seidler, Barbara; Gottschalk, Kathleen; Dobler, Melanie; Hieber, Maren; Arbeiter, Andreas; Klein, Sabine; Kong, Bo; Michalski, Christoph W.; Schlitter, Anna Melissa; Esposito, Irene; Kind, Alexander J.; Rad, Lena; Schnieke, Angelika E.; Baccarini, Manuela; Alessi, Dario R.; Rad, Roland; Schmid, Roland M.; Schneider, Guenter; Saur, Dieter.

    In: Cancer Cell, Vol. 23, No. 3, 2013, p. 406-420.

    Research output: Contribution to journalArticle

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    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

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    JF - Cancer Cell

    SN - 1535-6108

    IS - 3

    ER -