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TGIF1 functions as a tumor suppressor in pancreatic ductal adenocarcinoma
Parash Parajuli1, Purba Singh2, Zhe Wang2
1Cellular and Molecular Pathogenesis Division, Department of Pathology and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.
Abstract:
A prominent function of TGIF1 is suppression of transforming growth factor beta (TGF-β) signaling, whose inactivation is deemed instrumental to the progression of pancreatic ductal adenocarcinoma (PDAC), as exemplified by the frequent loss of the tumor suppressor gene SMAD4 in this malignancy. Surprisingly, we found that genetic inactivation of Tgif1 in the context of oncogenic Kras, KrasG12D , culminated in the development of highly aggressive and metastatic PDAC despite de-repressing TGF-β signaling. Mechanistic experiments show that TGIF1 associates with Twist1 and inhibits Twist1 expression and activity, and this function is suppressed in the vast majority of human PDACs by KrasG12D /MAPK-mediated TGIF1 phosphorylation. Ablating Twist1 in KrasG12D ;Tgif1KO mice completely blunted PDAC formation, providing the proof-of-principle that TGIF1 restrains KrasG12D -driven PDAC through its ability to antagonize Twist1. Collectively, these findings pinpoint TGIF1 as a potential tumor suppressor in PDAC and further suggest that sustained activation of TGF-β signaling might act to accelerate PDAC progression rather than to suppress its initiation.
Insights
TGIF1 normally suppresses transforming growth factor beta (TGF-β) signaling. However, its loss promotes aggressive pancreatic ductal adenocarcinoma (PDAC) by enabling Twist1, revealing TGIF1 as a potential PDAC tumor suppressor.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Transforming growth factor beta (TGF-β) signaling is crucial in pancreatic ductal adenocarcinoma (PDAC) progression.
- Loss of the tumor suppressor gene SMAD4 is common in PDAC.
- TGIF1's role in PDAC is not fully understood, despite its known function in TGF-β signaling suppression.
Purpose of the Study:
- To investigate the role of TGIF1 in Kras-driven pancreatic ductal adenocarcinoma (PDAC).
- To elucidate the mechanism by which TGIF1 influences PDAC development and metastasis.
- To determine if TGIF1 acts as a tumor suppressor in PDAC.
Main Methods:
- Genetic inactivation of Tgif1 in KrasG12D mouse models.
- Analysis of TGF-β signaling pathway activity.
- Investigation of TGIF1 interaction with Twist1.
- Assessment of Twist1 expression and activity.
- Pharmacological or genetic ablation of Twist1 in KrasG12D;Tgif1KO mice.
Main Results:
- Genetic inactivation of Tgif1 in KrasG12D mice led to aggressive, metastatic PDAC.
- TGIF1 was found to associate with and inhibit Twist1 expression and activity.
- KrasG12D/MAPK signaling phosphorylates TGIF1, suppressing its inhibitory function on Twist1 in human PDAC.
- Ablation of Twist1 completely prevented PDAC formation in KrasG12D;Tgif1KO mice.
- Sustained TGF-β signaling correlated with accelerated PDAC progression.
Conclusions:
- TGIF1 acts as a tumor suppressor in PDAC by antagonizing Twist1.
- KrasG12D/MAPK signaling promotes PDAC by inactivating TGIF1's tumor-suppressive function.
- Sustained TGF-β signaling may accelerate PDAC progression rather than suppress initiation.
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