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

Available for download on Saturday, December 31, 2022

Included in

Neoplasms Commons

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