Repression of the type I interferon pathway underlies MYC & KRAS-dependent evasion of NK & B cells in pancreatic ductal adenocarcinoma

Muthalagu, N. et al. (2020) Repression of the type I interferon pathway underlies MYC & KRAS-dependent evasion of NK & B cells in pancreatic ductal adenocarcinoma. Cancer Discovery, 10(6), pp. 872-887. (doi: 10.1158/2159-8290.CD-19-0620) (PMID:32200350) (PMCID:PMC7611248)

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Abstract

MYC is implicated in the development and progression of Pancreatic cancer, yet the precise level of MYC deregulation required to contribute to tumour development has been difficult to define. We used modestly elevated expression of human MYC, driven from the Rosa26 locus, to investigate the pancreatic phenotypes arising in mice from an approximation of MYC trisomy. We show that this level of MYC alone suffices to drive pancreatic neuroendocrine tumours, and to accelerate progression of KRAS-initiated precursor lesions to metastatic pancreatic ductal adenocarcinoma. Our phenotype exposed suppression of the Type I Interferon pathway by the combined actions of MYC and KRAS and we present evidence of repressive MYC/MIZ1 complexes binding directly to the promoters of type I Interferon regulators IRF5, IRF7, STAT1 and STAT2. De-repression of Interferon regulators allows pancreatic tumour infiltration of B and NK cells, resulting in increased survival.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Monteverde, Tiziana and Gyuraszova, Dr Katarina and Murphy, Professor Daniel and Neidler, Ms Sarah and Biankin, Professor Andrew and Nixon, Mr Colin and Coffelt, Dr Seth and Clark, Mr William and Rink, Curtis and Morton, Dr Jennifer and Wiesheu, Robert and Laing, Sarah and Kruspig, Dr Bjorn and Whyte, Declan and Karim, Ms Saadia and Sansom, Professor Owen
Authors: Muthalagu, N., Monteverde, T., Raffo-Iraolagoitia, X., Wiesheu, R., Whyte, D., Hedley, A., Laing, S., Kruspig, B., Upstill-Goddard, R., Shaw, R., Neidler, S., Rink, C., Karim, S. A., Gyuraszova, K., Nixon, C., Clark, W., Biankin, A. V., Carlin, L. M., Coffelt, S. B., Sansom, O. J., Morton, J. P., and Murphy, D. J.
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Cancer Discovery
Publisher:American Association for Cancer Research
ISSN:2159-8274
ISSN (Online):2159-8290
Published Online:21 March 2020
Copyright Holders:Copyright © 2020 American Association for Cancer Research
First Published:First published in Cancer Discovery 10(6): 872-887
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
168710SERPLUC: Suppression of Enzymes Required for Progression of Lung CancerDaniel MurphyEuropean Commission (EC)618448Institute of Cancer Sciences
172699NuSiCCDaniel MurphyEuropean Commission (EC)705190Institute of Cancer Sciences
168492A versatile spatio-temporally inducible genetically engineered mouse model of mesotheliomaDaniel MurphyBritish Lung Foundation (BLF)APHD13-5CS - Beatson Institute for Cancer Research
172121Funding SchemesAnna DominiczakWellcome Trust (WELLCOTR)105614/Z/14/ZInstitute of Cardiovascular & Medical Sciences
174115CRUK Centre RenewalOwen SansomCancer Research UK (CRUK)C7932/A25142CS - Beatson Institute for Cancer Research