- Email: [email protected]
115: Inactivation of TIF1g Cooperates with KrasG12D to Induce Cystic Tumors of the Pancreas
5es Journées scientifiques du CLARA
arrest of the cell cycle under CRMP5 blocade. Therefore, CRMP5 blocade inhibits GBM cell proliferation and may promote their escape from the homeostatic mechanisms of proliferation control. These results allow us to postulate that in GBM, CRMP5 may operate in pathways associated with stem-cell phenotype maintenance and/or cancer stem-like cell expansion related to Notch pathway. The characterization of intracellular marker to target tumor initiating cells specifically may have tremendous implications in the diagnosis and to target for more effective anti-cancer stem cell therapies. Remerciements : Contrat ANR-07 EMPB-010-01 pour financement CB Contrat Ligue contre le Cancer 2008.
115 Inactivation of TIF1g Cooperates with KrasG12D to Induce Cystic Tumors of the Pancreas David Vincent/Yan Kai-Ping/Treilleux Isabelle/Arfi Vanessa/ Kaniewski Bastien/Martel Sylvie/Goddard-Leon Sophie/ Bardeesy Nabeel/Puisieux Alain/Bartholin Laurent Inserm U590/IGBMC/Centre Léon-Bérard/Inserm U590/Inserm U590/ Centre Léon-Bérard/Centre Léon-Bérard/Havard/Inserm U590/Inserm U590 Contact : [email protected]
Inactivation of the Transforming Growth Factor Beta (TGFE) tumor suppressor pathway contributes to the progression of Pancreatic Ductal AdenoCarcinoma (PDAC). Transcriptional Intermediary Factor 1 gamma (TIF1J) has recently been proposed to be involved in TGFE signaling, functioning as either a positive or negative regulator of the pathway.
S90
Here, we addressed the role of TIF1J in pancreatic carcinogenesis. We generated conditional Tif1J knockout mice (Tif1Jlox/lox) to allow selective abrogation of Tif1J expression in the pancreas of Pdx1Cre; Tif1Jlox/lox mice. We also generated Pdx1-Cre; LSL-KrasG12D; Tif1Jlox/lox mice to address the effect of Tif1J loss-of-function in precancerous lesions induced by oncogenic KrasG12D. Finally, we analyzed TIF1J expression in human pancreatic tumors. In our mouse model, we showed that Tif1J was dispensable for normal pancreatic development but cooperated with Kras activation to induce pancreatic tumors reminiscent of human Intraductal Papillary Mucinous Neoplasms (IPMNs), a precursor to PDAC. 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 pseudoislets within the papillary projections, suggest that SMAD4 and TIF1J don’t have strictly redundant functions. Finally, we report that TIF1J expression is markedly down-regulated in human pancreatic tumors supporting the relevance of these findings to human malignancy. This study suggests that TIF1J is critical for tumor suppression in the pancreas, brings new insight into the etiology of pancreatic cancer and constitutes a promising model to decipher the respective roles of SMAD4 and TIF1J in the multifaceted functions of TGFE in carcinogenesis and development. Acknowledgements : We thank T. Jacks/R. DePinho, D. Tuveson, and D. Melton for providing Ink4A/Arflox/lox, LSL-KrasG12D, and Pdx1-Cre m
Bull Cancer vol. 97 • N° spécial • mars 2010
arrest of the cell cycle under CRMP5 blocade. Therefore, CRMP5 blocade inhibits GBM cell proliferation and may promote their escape from the homeostatic mechanisms of proliferation control. These results allow us to postulate that in GBM, CRMP5 may operate in pathways associated with stem-cell phenotype maintenance and/or cancer stem-like cell expansion related to Notch pathway. The characterization of intracellular marker to target tumor initiating cells specifically may have tremendous implications in the diagnosis and to target for more effective anti-cancer stem cell therapies. Remerciements : Contrat ANR-07 EMPB-010-01 pour financement CB Contrat Ligue contre le Cancer 2008.
115 Inactivation of TIF1g Cooperates with KrasG12D to Induce Cystic Tumors of the Pancreas David Vincent/Yan Kai-Ping/Treilleux Isabelle/Arfi Vanessa/ Kaniewski Bastien/Martel Sylvie/Goddard-Leon Sophie/ Bardeesy Nabeel/Puisieux Alain/Bartholin Laurent Inserm U590/IGBMC/Centre Léon-Bérard/Inserm U590/Inserm U590/ Centre Léon-Bérard/Centre Léon-Bérard/Havard/Inserm U590/Inserm U590 Contact : [email protected]
Inactivation of the Transforming Growth Factor Beta (TGFE) tumor suppressor pathway contributes to the progression of Pancreatic Ductal AdenoCarcinoma (PDAC). Transcriptional Intermediary Factor 1 gamma (TIF1J) has recently been proposed to be involved in TGFE signaling, functioning as either a positive or negative regulator of the pathway.
S90
Here, we addressed the role of TIF1J in pancreatic carcinogenesis. We generated conditional Tif1J knockout mice (Tif1Jlox/lox) to allow selective abrogation of Tif1J expression in the pancreas of Pdx1Cre; Tif1Jlox/lox mice. We also generated Pdx1-Cre; LSL-KrasG12D; Tif1Jlox/lox mice to address the effect of Tif1J loss-of-function in precancerous lesions induced by oncogenic KrasG12D. Finally, we analyzed TIF1J expression in human pancreatic tumors. In our mouse model, we showed that Tif1J was dispensable for normal pancreatic development but cooperated with Kras activation to induce pancreatic tumors reminiscent of human Intraductal Papillary Mucinous Neoplasms (IPMNs), a precursor to PDAC. 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 pseudoislets within the papillary projections, suggest that SMAD4 and TIF1J don’t have strictly redundant functions. Finally, we report that TIF1J expression is markedly down-regulated in human pancreatic tumors supporting the relevance of these findings to human malignancy. This study suggests that TIF1J is critical for tumor suppression in the pancreas, brings new insight into the etiology of pancreatic cancer and constitutes a promising model to decipher the respective roles of SMAD4 and TIF1J in the multifaceted functions of TGFE in carcinogenesis and development. Acknowledgements : We thank T. Jacks/R. DePinho, D. Tuveson, and D. Melton for providing Ink4A/Arflox/lox, LSL-KrasG12D, and Pdx1-Cre m
Bull Cancer vol. 97 • N° spécial • mars 2010