Dynamic ROS control by TIGAR regulates the initiation and progression of pancreatic cancer
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Eric Cheung Gina M DeNicola Colin Nixon Karen Blyth Stiaan Labuschagne David A Tuveson Karen VousdenAbstract
The TIGAR protein has antioxidant activity that supports intestinal tissue repair and adenoma development. Using a pancreatic ductal adenocarcinoma (PDAC) model, we show that reactive oxygen species (ROS) regulation by TIGAR supports premalignant tumor initiation while restricting metastasis. Increased ROS in PDAC cells drives a phenotypic switch that increases migration, invasion, and metastatic capacity. This switch is dependent on increased activation of MAPK signaling and can be reverted by antioxidant treatment. In mouse and human, TIGAR expression is modulated during PDAC development, with higher TIGAR levels in premalignant lesions and lower TIGAR levels in metastasizing tumors. Our study indicates that temporal, dynamic control of ROS underpins full malignant progression and helps to rationalize conflicting reports of pro- and anti-tumor effects of antioxidant treatment.
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Journal Cancer Cell
Volume 37
Issue number 2
Pages 168-182
Available online
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Publisher website (DOI) 10.1016/j.ccell.2019.12.012
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Europe PubMed Central 31983610
Pubmed 31983610
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