Antagonism between Prdm16 and Smad4 specifies the trajectory and progression of pancreatic cancer
Abstract
The transcription factor Prdm16 functions as a potent suppressor of transforming growth factor-beta (TGF-β) signaling, whose inactivation is deemed essential to the progression of pancreatic ductal adenocarcinoma (PDAC). Using the KrasG12D-based mouse model of human PDAC, we surprisingly found that ablating Prdm16 did not block but instead accelerated PDAC formation and progression, suggesting that Prdm16 might function as a tumor suppressor in this malignancy. Subsequent genetic experiments showed that ablating Prdm16 along with Smad4 resulted in a shift from a well-differentiated and confined neoplasm to a highly aggressive and metastatic disease, which was associated with a striking deviation in the trajectory of the premalignant lesions. Mechanistically, we found that Smad4 interacted with and recruited Prdm16 to repress its own expression, therefore pinpointing a model in which Prdm16 functions downstream of Smad4 to constrain the PDAC malignant phenotype. Collectively, these findings unveil an unprecedented antagonistic interaction between the tumor suppressors Smad4 and Prdm16 that functions to restrict PDAC progression and metastasis.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 24, 2023
- Source ID
- 10.1083/jcb.202203036
Entities
People
- Allyn Austin Bryan
- Azeddine Atfi
- Creighton Friend
- Céline Prunier
- Deanna J. Campbell
- Eric Hurwitz
- Keli Xu
- Mohammed S Razzaque
- Parash Parajuli
- Seval Ozkan
- Steven C Smith
- Thien Ly Nguyen
- Ting-Xuan Lu
Organizations
- Centre de recherche Saint-Antoine
- Lake Erie College of Osteopathic Medicine
- National Cancer Institute
- National Institutes of Health
- United States Department of Defense
- University of Mississippi
- VCU Massey Cancer Center
- Virginia Commonwealth University