Notch3 drives development and progression of cholangiocarcinoma

Guest, R. V. et al. (2016) Notch3 drives development and progression of cholangiocarcinoma. Proceedings of the National Academy of Sciences of the United States of America, 113(43), pp. 12250-12255. (doi:10.1073/pnas.1600067113) (PMID:27791012) (PMCID:PMC5086988)

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Abstract

The prognosis of cholangiocarcinoma (CC) is dismal. Notch has been identified as a potential driver; forced exogenous overexpression of Notch1 in hepatocytes results in the formation of biliary tumors. In human disease, however, it is unknown which components of the endogenously signaling pathway are required for tumorigenesis, how these orchestrate cancer, and how they can be targeted for therapy. Here we characterize Notch in human-resected CC, a toxin-driven model in rats, and a transgenic mouse model in which p53 deletion is targeted to biliary epithelia and CC induced using the hepatocarcinogen thioacetamide. We find that across species, the atypical receptor NOTCH3 is differentially overexpressed; it is progressively up-regulated with disease development and promotes tumor cell survival via activation of PI3k-Akt. We use genetic KO studies to show that tumor growth significantly attenuates after Notch3 deletion and demonstrate signaling occurs via a noncanonical pathway independent of the mediator of classical Notch, Recombinant Signal Binding Protein for Immunoglobulin Kappa J Region (RBPJ). These data present an opportunity in this aggressive cancer to selectively target Notch, bypassing toxicities known to be RBPJ dependent.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Morton, Dr Jennifer and Sansom, Professor Owen
Authors: Guest, R. V., Boulter, L., Dwyer, B. J., Kendall, T. J., Man, T.-Y., Minnis-Lyons, S. E., Lu, W.-Y., Robson, A. J., Gonzalez, S. F., Raven, A., Wojtacha, D., Morton, J. P., Komuta, M., Roskams, T., Wigmore, S. J., Sansom, O. J., and Forbes, S. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Academy of Sciences
ISSN:0027-8424
ISSN (Online):1091-6490
Copyright Holders:Copyright © 2016 National Academy of Sciences
First Published:First published in Proceedings of the National Academy of Sciences of the United States of America 113(43):12250-12255
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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