DOI
https://doi.org/10.25772/2TKW-9021
Defense Date
2020
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Clinical and Translational Sciences
First Advisor
Steven R. Grossman
Second Advisor
Kristoffer Valerie
Third Advisor
Anthony C. Faber
Fourth Advisor
J. Chuck Harrell
Fifth Advisor
Bhaumik Patel
Abstract
The transcriptional coregulator CtBP2 has been implicated as an oncogene in colon, prostate, breast and ovarian cancers. Previously, we reported overexpression of CtBP2 in human PDAC specimens. However, its exact role in PDAC is still unclear. In the current study, we attempt to delineate the oncogenic role CtBP2 in PDAC growth and metastasis. Using an orthotopic syngeneic pancreatic tumor mouse model (CKP), we found that deletion of Ctbp2 decreases PDAC tumor growth, proliferation, metastasis, EMT and significantly prolongs survival. Further, we identified significant downregulation of Erbb3 mRNA levels upon deletion of Ctbp2 in CKP PDAC cells As ErbB3 signaling was previously reported to play a critical role in pancreatic tumorigenesis, we hypothesized that CtBP2 regulation of ErbB3 signaling at least, in part, contributes to PDAC growth and metastasis. Upon mechanistic exploration, we found that CtBP2 interactor and Erbb3 regulator, Znp217, was concomitantly downregulated upon deletion of Ctbp2. On the other hand, tumors obtained from Ctbp2 KO cohort showed a significant increase in E-cadherin levels, recalling previous findings in breast cancer, and suggesting a possible role of CtBP2 in epithelial-mesenchymal transition (EMT) in PDAC cells. Our findings establish a dual oncogenic role of CtBP2 in PDAC growth, including through ErbB3/PI3K regulation as well as EMT/metastasis via regulation of E-cadherin/PI3K signaling. In vitro studies demonstrated increased cytotoxicity upon combining CtBP2 chemical inhibitors with ErbB3/PI3K inhibitors. Our findings suggest new avenues to test CtBP2 inhibitors in combination with effective ErbB3 or PI3K inhibitors as a novel treatment strategy to tackle metastatic PDAC.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-15-2020