TY - JOUR
T1 - Inactivation of TIF1γ cooperates with KrasG12D to induce cystic tumors of the pancreas
AU - Vincent, David F.
AU - Yan, Kai Ping
AU - Treilleux, Isabelle
AU - Gay, Fabien
AU - Arfi, Vanessa
AU - Kaniewsky, Bastien
AU - Marie, Julien C.
AU - Lepinasse, Florian
AU - Martel, Sylvie
AU - Goddard-Leon, Sophie
AU - Iovanna, Juan L.
AU - Dubus, Pierre
AU - Garcia, Stéphane
AU - Puisieux, Alain
AU - Rimokh, Ruth
AU - Bardeesy, Nabeel
AU - Scoazec, Jean Yves
AU - Losson, Régine
AU - Bartholin, Laurent
PY - 2009/1/1
Y1 - 2009/1/1
N2 - Inactivation of the Transforming Growth Factor Beta (TGFβ) tumor suppressor pathway contributes to the progression of Pancreatic Ductal AdenoCarcinoma (PDAC) since it is inactivated in virtually all cases of this malignancy. Genetic lesions inactivating this pathway contribute to pancreatic tumor progression in mouse models. Transcriptional Intermediary Factor 1 gamma (TIF1γ) has recently been proposed to be involved in TGFβ signaling, functioning as either a positive or negative regulator of the pathway. Here, we addressed the role of TIF1γ in pancreatic carcinogenesis. Using conditional TIF1γ knockout mice (TIF1γlox/lox), we selectively abrogated TIF1γ expression in the pancreas of Pdx1-Cre;TIF1γlox/lox mice. We also generated Pdx1-Cre;LSL- KrasG12D;TIF1γlox/lox mice to address the effect of TIF1γ loss-of-function in precancerous lesions induced by oncogenic Kras G12D. Finally, we analyzed TIF1γ expression in human pancreatic tumors. In our mouse model, we showed that TIF1γ was dispensable for normal pancreatic development but cooperated with Kras activation to induce pancreatic tumors reminiscent of human Intraductal Papillary Mucinous Neoplasms (IPMNs). Interestingly, these cystic lesions resemble those observed in Pdx1-Cre;LSL-KrasG12D;Smad4lox/lox mice described by others. However, distinctive characteristics, such as the systematic presence of endocrine pseudo-islets within the papillary projections, suggest that SMAD4 and TIF1γ don't have strictly redundant functions. Finally, we report that TIF1γ expression is markedly downregulated in human pancreatic tumors by quantitative RT-PCR and immunohistochemistry supporting the relevance of these findings to human malignancy. This study suggests that TIF1γ is critical for tumor suppression in the pancreas, brings new insight into the genetics of pancreatic cancer, and constitutes a promising model to decipher the respective roles of SMAD4 and TIF1γ in the multifaceted functions of TGFβ in carcinogenesis and development.
AB - Inactivation of the Transforming Growth Factor Beta (TGFβ) tumor suppressor pathway contributes to the progression of Pancreatic Ductal AdenoCarcinoma (PDAC) since it is inactivated in virtually all cases of this malignancy. Genetic lesions inactivating this pathway contribute to pancreatic tumor progression in mouse models. Transcriptional Intermediary Factor 1 gamma (TIF1γ) has recently been proposed to be involved in TGFβ signaling, functioning as either a positive or negative regulator of the pathway. Here, we addressed the role of TIF1γ in pancreatic carcinogenesis. Using conditional TIF1γ knockout mice (TIF1γlox/lox), we selectively abrogated TIF1γ expression in the pancreas of Pdx1-Cre;TIF1γlox/lox mice. We also generated Pdx1-Cre;LSL- KrasG12D;TIF1γlox/lox mice to address the effect of TIF1γ loss-of-function in precancerous lesions induced by oncogenic Kras G12D. Finally, we analyzed TIF1γ expression in human pancreatic tumors. In our mouse model, we showed that TIF1γ was dispensable for normal pancreatic development but cooperated with Kras activation to induce pancreatic tumors reminiscent of human Intraductal Papillary Mucinous Neoplasms (IPMNs). Interestingly, these cystic lesions resemble those observed in Pdx1-Cre;LSL-KrasG12D;Smad4lox/lox mice described by others. However, distinctive characteristics, such as the systematic presence of endocrine pseudo-islets within the papillary projections, suggest that SMAD4 and TIF1γ don't have strictly redundant functions. Finally, we report that TIF1γ expression is markedly downregulated in human pancreatic tumors by quantitative RT-PCR and immunohistochemistry supporting the relevance of these findings to human malignancy. This study suggests that TIF1γ is critical for tumor suppression in the pancreas, brings new insight into the genetics of pancreatic cancer, and constitutes a promising model to decipher the respective roles of SMAD4 and TIF1γ in the multifaceted functions of TGFβ in carcinogenesis and development.
UR - http://www.scopus.com/inward/record.url?scp=68249108045&partnerID=8YFLogxK
U2 - 10.1371/journal.pgen.1000575
DO - 10.1371/journal.pgen.1000575
M3 - Article
C2 - 19629168
AN - SCOPUS:68249108045
SN - 1553-7390
VL - 5
JO - PLoS Genetics
JF - PLoS Genetics
IS - 7
M1 - e1000575
ER -