DOI
https://doi.org/10.25772/EDF8-ZV91
Defense Date
2017
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Clinical and Translational Sciences
First Advisor
Steven R Grossman
Second Advisor
Larisa Litovchick
Third Advisor
Ross Mikkelsen
Fourth Advisor
Anthony Faber
Fifth Advisor
Bhaumik Patel
Abstract
The C terminal binding proteins (CtBP) 1 and 2 are a family of transcriptional co-repressors overexpressed in a variety of cancers, and are frequently associated with poor prognosis and chemoresistance. CtBP has also been characterized in cell culture models as drivers of migration/invasion and epithelial-mesenchymal transition. CtBP mediates its transcriptional corepressor activity via its dehydrogenase domain, and inhibition of this domain interferes with CtBP oncogenic functions. The role of CtBP in APC mutant neoplasia remains obscure even though APC is responsible for degradation of both β-catenin and CtBP in suppressing colorectal tumorigenesis. Our prior work demonstrated that CtBP proteins can be effectively therapeutically targeted with substrate analogues of their intrinsic dehydrogenase domains. In addition, CtBP2 has been reported to play an important role in human colon cancer stem cells via its interaction with the transcription factor TCF4 on chromatin and promotes self-renewal of human colon tumor initiating cells (TICs) in vitro. To study CtBP2’s role in TIC activity in vivo, we studied TIC’s from Apc min/+ mice, which exhibit massive intestinal polyposis, in Ctbp2 wildtype or haploinsufficient backgrounds. Indeed, LGR5+, CD44+/CD24+, and CD133+ TIC populations were substantially decreased in Apc min/+ Ctbp2 +/- vs. Apc min/+ intestinal epithelia. Validating CtBP as a therapeutic target for TIC activity, we investigated intestinal TIC populations and polyposis in Apc Min/+ mice treated with the CtBP inhibitor 4-chloro-hydroxyimino phenylpyruvate (4-Cl-HIPP). Like Ctbp2 haploinsufficiency, 4-Cl-HIPP significantly decreased intestinal polyposis and downregulated LGR5+, CD44+/CD24+, and CD133+ TIC populations. To understand if CtBP2’s role in TIC activity and tumor progression extended to a cancer model, we studied the impact of Ctbp2 gene dosage in a mutant KRAS mouse pancreatic ductal adenocarcinoma (PDAC) model (CKP). Ctbp2 haploinsufficiency remarkably prolonged survival, abrogated peritoneal metastasis and ascites, and caused dramatic downregulation of c-Myc, a known critical dependency for TIC activity and tumor progression in PDAC. Overall, our data suggest a key role of CtBP2 in driving the TIC compartment and progression in both pre-malignant intestinal polyposis and aggressive murine PDAC models.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
12-11-2017