Defense Date
2025
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Human Genetics
First Advisor
Azeddine Atfi
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is known for its poor survival and limited treatment options. Identifying novel molecular mechanisms is therefore critical to uncover new therapeutic targets. Previous studies suggest that TGIF1 may function as a tumor suppressor in PDAC by promoting apoptosis, a form of programmed cell death. In contrast, MLKL, the executioner of necroptosis, has an unclear role in PDAC. Interestingly, we observed a growth defect in mouse pups with TGIF1 overexpression and MLKL knockout, suggesting a functional connection.
This study aimed to investigate the potential interaction between TGIF1 and MLKL in PDAC. To characterize necrosulfonamide (NSA)-induced high-molecular-weight (HMW) TGIF1, we mutated cysteine residues and performed mass spectrometry to identify its binding partners. To explore MLKL’s role in PDAC, we used MLKL knockout GEMMs, public datasets, and inducible Kras models.
Our findings show that HMW TGIF1 forms through cysteine residues, particularly C83, and binds to a candidate identified by mass spectrometry. MLKL deletion delayed PDAC initiation but did not prevent tumor development. Kras activation enhanced MLKL protein expression. In vivo, MLKL overexpression promoted PDAC when Kras was on but suppressed growth when Kras was off.
Together, these results suggest TGIF1 and MLKL have context-dependent roles in PDAC, with potential therapeutic implications.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
9-10-2025