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Tif1γ suppresses murine pancreatic tumoral transformation by a Smad4-independent pathway
David F Vincent1, Johann Gout, Nicolas Chuvin
1INSERM U1052, Cancer Research Center of Lyon (CRCL), Lyon, France.
Abstract:
Transcriptional intermediary factor 1γ (TIF1γ; alias, TRIM33/RFG7/PTC7/ectodermin) belongs to an evolutionarily conserved family of nuclear factors that have been implicated in stem cell pluripotency, embryonic development, and tumor suppression. TIF1γ expression is markedly down-regulated in human pancreatic tumors, and Pdx1-driven Tif1γ inactivation cooperates with the Kras(G12D) oncogene in the mouse pancreas to induce intraductal papillary mucinous neoplasms. In this study, we report that aged Pdx1-Cre; LSL-Kras(G12D); Tif1γ(lox/lox) mice develop pancreatic ductal adenocarcinomas (PDACs), an aggressive and always fatal neoplasm, demonstrating a Tif1γ tumor-suppressive function in the development of pancreatic carcinogenesis. Deletion of SMAD4/DPC4 (deleted in pancreatic carcinoma locus 4) occurs in approximately 50% of human cases of PDAC. We, therefore, assessed the genetic relationship between Tif1γ and Smad4 signaling in pancreatic tumors and found that Pdx1-Cre; LSL-Kras(G12D); Smad4(lox/lox); Tif1γ(lox/lox) (alias, KSSTT) mutant mice exhibit accelerated tumor progression. Consequently, Tif1γ tumor-suppressor effects during progression from a premalignant to a malignant state in our mouse model of pancreatic cancer are independent of Smad4. These findings establish, for the first time to our knowledge, that Tif1γ and Smad4 both regulate an intraductal papillary mucinous neoplasm-to-PDAC sequence through distinct tumor-suppressor programs.
Insights
Transcriptional intermediary factor 1γ (TIF1γ) acts as a tumor suppressor in pancreatic cancer. Its inactivation promotes tumor development, and its function is independent of Smad4 signaling in this aggressive disease.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Transcriptional intermediary factor 1γ (TIF1γ) is a nuclear factor involved in stem cell pluripotency, embryonic development, and tumor suppression.
- TIF1γ expression is reduced in human pancreatic tumors, and its inactivation cooperates with Kras(G12D) to promote pancreatic neoplasms.
Purpose of the Study:
- To investigate the tumor-suppressive role of TIF1γ in pancreatic carcinogenesis.
- To determine the genetic relationship between TIF1γ and Smad4 signaling in pancreatic tumor progression.
Main Methods:
- Utilized a mouse model (Pdx1-Cre; LSL-Kras(G12D); Tif1γ(lox/lox)) to study pancreatic ductal adenocarcinoma (PDAC) development.
- Assessed tumor progression in mice with combined inactivation of Tif1γ and Smad4 (Pdx1-Cre; LSL-Kras(G12D); Smad4(lox/lox); Tif1γ(lox/lox)).
Main Results:
- Aged mice with Tif1γ inactivation developed PDAC, confirming its tumor-suppressive function.
- Combined inactivation of Tif1γ and Smad4 accelerated tumor progression, indicating Tif1γ's role is independent of Smad4.
- TIF1γ and Smad4 regulate the transition from premalignant lesions to PDAC through distinct tumor-suppressor pathways.
Conclusions:
- TIF1γ is a critical tumor suppressor in pancreatic cancer development and progression.
- TIF1γ and Smad4 act independently to control the sequence from intraductal papillary mucinous neoplasms to PDAC.
- These findings elucidate distinct tumor-suppressor programs in pancreatic carcinogenesis.
