Journal
CANCER CELL
Volume 37, Issue 2, Pages 168-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2019.12.012
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Funding
- Cancer Research UK [C596/A10419, C596/A26855, FC001557, C596/A17196]
- Francis Crick Institute
- UK Medical Research Council [001557]
- Wellcome Trust [001557]
- CRUK Beatson Institute
- Cold Spring Harbor Laboratory Association
- V Foundation
- National Institutes of Health [NIH 5P30CA45508, 5P50CA101955, P20CA192996, 1U10CA180944, U01CA224013, U01CA210240-01A1, 1R01CA188134, 1R01CA190092]
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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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