Inactivation of TIF1γ Cooperates with KrasG12D to Induce Cystic Tumors of the Pancreas

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 KrasG12D. 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 down-regulated 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.
Author Summary Inactivation of the TGFβ tumor suppressor pathway contributes to the progression of Pancreatic Ductal AdenoCarcinoma (PDAC), a devastating malignancy. Transcriptional Intermediary Factor 1γ (TIF1γ) has recently been proposed to be involved in TGFβ signaling, a pathway inactivated in virtually all cases of this malignancy. To address the role of TIF1γ in pancreatic carcinogenesis, we used conditional Tif1γ knockout mice. In a genetic background expressing a constitutively active mutation of KRAS oncogene (KrasG12D) recurrently found in patients with PDAC, Tif1γ inactivation induces pancreatic precancerous lesions resembling those observed in the absence of Smad4, a key player involved TGFβ signal transduction. This observation strengthens the notion that TIF1γ plays an active role in TGFβ signaling. Interestingly, we also found that TIF1γ expression was markedly down-regulated in human pancreatic tumors supporting the relevance of our findings to human malignancy. Characterization of new players involved in the outbreak of early pancreatic lesions that will eventually evolve into invasive pancreatic cancer is crucial to detect the disease earlier and eventually develop new therapeutic drugs.