Date of Award

2023

Document Type

Open Access Master's Report

Degree Name

Master of Science in Biological Sciences (MS)

Administrative Home Department

Department of Biological Sciences

Advisor 1

Xiaohu Tang

Committee Member 1

Paul Goetsch

Committee Member 2

Stephen Techtmann

Abstract

Pancreatic ductal adenocarcinoma (PDAC), the fourth leading cause of US cancer-related deaths, has a stark 5-year survival rate of 9%, emphasizing an urgent need for effective therapies. A well-established characteristic of cancer, metabolic dysregulation, presents an opportunity for developing therapies that target specific metabolic susceptibilities inherent in cancer cells. Our recent studies have discovered a susceptibility in PDAC; deprivation of cystine or blocking its uptake by erastin (a cystine transport inhibitor) triggers significant lipid peroxidation, thereby inducing ferroptosis specifically in the mesenchymal subtype of PDAC, but not in the epithelial subtype. This study aims to elucidate the roles of Selenoprotein P (Sepp1) and Thioredoxin Reductase (TrxR) in epithelial PDAC. Using RNAi and CRISPR-CAS9 methodologies, we found that the activity of TrxR2 is responsible for drug resistance in epithelial PDAC, while Sepp1 and TrxR1 are unnecessary. These findings could significantly contribute to novel therapeutic developments.

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