Concomitant Pancreatic Activation of KrasG12D and Tgfa Results in Cystic Papillary Neoplasms Reminiscent of Human IPMN

Jens T. Siveke; Henrik Einwächter; Bence Sipos; Clara Lubeseder-Martellato; Günter Klöppel; Roland M. Schmid

doi:10.1016/j.ccr.2007.08.002

Concomitant Pancreatic Activation of Kras^G12D and Tgfa Results in Cystic Papillary Neoplasms Reminiscent of Human IPMN

Jens T. Siveke, Henrik Einwächter, Bence Sipos, Clara Lubeseder-Martellato, Günter Klöppel, Roland M. Schmid

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Abstract

Growth factors have been implicated in pancreatic carcinogenesis. In this study we analyzed the effect of Tgfa overexpression in addition to mutant Kras^G12D by crossing Elastase-Tgfa mice with p48^+/Cre;Kras^+/LSL-G12D mice. We show that concomitant expression of TGFα and Kras^G12D accelerates the progression of mPanIN lesions to metastatic pancreatic cancer and leads to the development of cystic papillary lesions resembling human intraductal papillary mucinous neoplasms (IPMN). Microarray data in mice revealed an IPMN signature and IPMNs expressed MUC1 and MUC5AC but not MUC2, similar to human pancreatobiliary IPMNs. Invasive ductal adenocarcinoma developed from PanINs and IPMNs, suggesting precursor lines for both lesion types in this model. In conclusion, Egfr signaling in synergy with oncogenic Kras may be a prerequisite for IPMN development and progression to pancreatic cancer.

Originalsprache	Englisch
Seiten (von - bis)	266-279
Seitenumfang	14
Fachzeitschrift	Cancer Cell
Jahrgang	12
Ausgabenummer	3
DOIs	https://doi.org/10.1016/j.ccr.2007.08.002
Publikationsstatus	Veröffentlicht - 11 Sept. 2007

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title = "Concomitant Pancreatic Activation of KrasG12D and Tgfa Results in Cystic Papillary Neoplasms Reminiscent of Human IPMN",

abstract = "Growth factors have been implicated in pancreatic carcinogenesis. In this study we analyzed the effect of Tgfa overexpression in addition to mutant KrasG12D by crossing Elastase-Tgfa mice with p48+/Cre;Kras+/LSL-G12D mice. We show that concomitant expression of TGFα and KrasG12D accelerates the progression of mPanIN lesions to metastatic pancreatic cancer and leads to the development of cystic papillary lesions resembling human intraductal papillary mucinous neoplasms (IPMN). Microarray data in mice revealed an IPMN signature and IPMNs expressed MUC1 and MUC5AC but not MUC2, similar to human pancreatobiliary IPMNs. Invasive ductal adenocarcinoma developed from PanINs and IPMNs, suggesting precursor lines for both lesion types in this model. In conclusion, Egfr signaling in synergy with oncogenic Kras may be a prerequisite for IPMN development and progression to pancreatic cancer.",

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author = "Siveke, {Jens T.} and Henrik Einw{\"a}chter and Bence Sipos and Clara Lubeseder-Martellato and G{\"u}nter Kl{\"o}ppel and Schmid, {Roland M.}",

note = "Funding Information: We thank D.A. Tuveson, D.A. Melton, and E.P. Sandgren for the generous gift of transgenic mice and D.A. Tuveson for providing Mist1-Kras sections. We are grateful to O. Strobel and S. Thayer for supplying the Shh image. We thank J. Mages for his help in performing gene-profiling experiments and M. Neuhofer and C. K{\"o}hler for excellent technical assistance. This work was in part supported by grants from Deutsche Krebshilfe (#107195; J.T.S. and R.M.S.) and the Association for International Cancer Research (07-0543; J.T.S.). ",

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T1 - Concomitant Pancreatic Activation of KrasG12D and Tgfa Results in Cystic Papillary Neoplasms Reminiscent of Human IPMN

AU - Siveke, Jens T.

AU - Einwächter, Henrik

AU - Sipos, Bence

AU - Lubeseder-Martellato, Clara

AU - Klöppel, Günter

AU - Schmid, Roland M.

N1 - Funding Information: We thank D.A. Tuveson, D.A. Melton, and E.P. Sandgren for the generous gift of transgenic mice and D.A. Tuveson for providing Mist1-Kras sections. We are grateful to O. Strobel and S. Thayer for supplying the Shh image. We thank J. Mages for his help in performing gene-profiling experiments and M. Neuhofer and C. Köhler for excellent technical assistance. This work was in part supported by grants from Deutsche Krebshilfe (#107195; J.T.S. and R.M.S.) and the Association for International Cancer Research (07-0543; J.T.S.).

PY - 2007/9/11

Y1 - 2007/9/11

N2 - Growth factors have been implicated in pancreatic carcinogenesis. In this study we analyzed the effect of Tgfa overexpression in addition to mutant KrasG12D by crossing Elastase-Tgfa mice with p48+/Cre;Kras+/LSL-G12D mice. We show that concomitant expression of TGFα and KrasG12D accelerates the progression of mPanIN lesions to metastatic pancreatic cancer and leads to the development of cystic papillary lesions resembling human intraductal papillary mucinous neoplasms (IPMN). Microarray data in mice revealed an IPMN signature and IPMNs expressed MUC1 and MUC5AC but not MUC2, similar to human pancreatobiliary IPMNs. Invasive ductal adenocarcinoma developed from PanINs and IPMNs, suggesting precursor lines for both lesion types in this model. In conclusion, Egfr signaling in synergy with oncogenic Kras may be a prerequisite for IPMN development and progression to pancreatic cancer.

AB - Growth factors have been implicated in pancreatic carcinogenesis. In this study we analyzed the effect of Tgfa overexpression in addition to mutant KrasG12D by crossing Elastase-Tgfa mice with p48+/Cre;Kras+/LSL-G12D mice. We show that concomitant expression of TGFα and KrasG12D accelerates the progression of mPanIN lesions to metastatic pancreatic cancer and leads to the development of cystic papillary lesions resembling human intraductal papillary mucinous neoplasms (IPMN). Microarray data in mice revealed an IPMN signature and IPMNs expressed MUC1 and MUC5AC but not MUC2, similar to human pancreatobiliary IPMNs. Invasive ductal adenocarcinoma developed from PanINs and IPMNs, suggesting precursor lines for both lesion types in this model. In conclusion, Egfr signaling in synergy with oncogenic Kras may be a prerequisite for IPMN development and progression to pancreatic cancer.

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