Dynamic ROS control by TIGAR regulates the initiation and progression of pancreatic cancer

Cheung, E. C., DeNicola, G. M., Nixon, C., Blyth, K. , Labuschagne, C. F., Tuveson, D. A. and Vousden, K. (2020) Dynamic ROS control by TIGAR regulates the initiation and progression of pancreatic cancer. Cancer Cell, 37(2), 168-182.e4. (doi: 10.1016/j.ccell.2019.12.012) (PMID:31983610) (PMCID:PMC7008247)

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Abstract

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. [Abstract copyright: Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.]

Item Type:Articles
Additional Information:This work was funded by Cancer Research UK grants C596/A10419 and C596/A26855 and supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001557), the UK Medical Research Council (001557), and the Wellcome Trust (001557), and the CRUK Beatson Institute, which receives its core funding from Cancer Research UK grant C596/A17196. D.A.T. is a distinguished scholar of the Lustgarten Foundation and director of the Lustgarten Foundation-designated Laboratory of Pancreatic Cancer Research. D.A.T. is also supported by the Cold Spring Harbor Laboratory Association, the V Foundation, and the National Institutes of Health (NIH 5P30CA45508, 5P50CA101955, P20CA192996, 1U10CA180944, U01CA224013, U01CA210240-01A1, 1R01CA188134, and 1R01CA190092).
Keywords:ERK, PDAC, ROS regulation, TIGAR, metastasis.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Blyth, Professor Karen and Cheung, Mr Eric and Nixon, Mr Colin and Labuschagne, Dr Christiaan Fred and Vousden, Karen
Creator Roles:
Blyth, K.Investigation, Supervision
Authors: Cheung, E. C., DeNicola, G. M., Nixon, C., Blyth, K., Labuschagne, C. F., Tuveson, D. A., and Vousden, K.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Cancer Cell
Publisher:Elsevier
ISSN:1535-6108
ISSN (Online):1878-3686
Published Online:23 January 2020
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in Cancer Cell 37:168-182
Publisher Policy:Reproduced under a Creative Commons License

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