Suppression of mutant Kirsten-RAS (KRASG12D)-driven pancreatic carcinogenesis by dual-specificity MAP kinase phosphatases 5 and 6

Kidger, A. M. et al. (2022) Suppression of mutant Kirsten-RAS (KRASG12D)-driven pancreatic carcinogenesis by dual-specificity MAP kinase phosphatases 5 and 6. Oncogene, 41(20), pp. 2811-2823. (doi: 10.1038/s41388-022-02302-0) (PMID:35418690) (PMCID:PMC9106580)

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Abstract

The cytoplasmic phosphatase DUSP6 and its nuclear counterpart DUSP5 are negative regulators of RAS/ERK signalling. Here we use deletion of either Dusp5 or Dusp6 to explore the roles of these phosphatases in a murine model of KRASG12D-driven pancreatic cancer. By 56-days, loss of either DUSP5 or DUSP6 causes a significant increase in KRASG12D-driven pancreatic hyperplasia. This is accompanied by increased pancreatic acinar to ductal metaplasia (ADM) and the development of pre-neoplastic pancreatic intraepithelial neoplasia (PanINs). In contrast, by 100-days, pancreatic hyperplasia is reversed with significant atrophy of pancreatic tissue and weight loss observed in animals lacking either DUSP5 or DUSP6. On further ageing, Dusp6−/− mice display accelerated development of metastatic pancreatic ductal adenocarcinoma (PDAC), while in Dusp5−/− animals, although PDAC development is increased this process is attenuated by atrophy of pancreatic acinar tissue and severe weight loss in some animals before cancer could progress. Our data suggest that despite a common target in the ERK MAP kinase, DUSP5 and DUSP6 play partially non-redundant roles in suppressing oncogenic KRASG12D signalling, thus retarding both tumour initiation and progression. Our data suggest that loss of either DUSP5 or DUSP6, as observed in certain human tumours, including the pancreas, could promote carcinogenesis.

Item Type:Articles
Additional Information:SMK was supported by a Cancer Research UK Programme Grant (C8227/A12053), an MRC Research Grant (MR/N020790/1 to SMK and CJC) and a Dundee Cancer Centre Studentship (to AMK), JPM and OJS are supported by Cancer Research UK (A25142, A17196, A21139, A29996 and A25233). BH and K-PJ are supported by grant 111822 from Deutsche Krebshilfe e.V. (German Cancer Aid) and LAK is supported by the German Research Council (DFG) through collaborative Research Centre 1321 (SFB1321).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Morton, Professor Jen and Sansom, Professor Owen
Authors: Kidger, A. M., Saville, M. K., Rushworth, L. K., Davidson, J., Stellzig, J., Ono, M., Kuebelsbeck, L. A., Janssen, K.-P., Holzmann, B., Morton, J. P., Sansom, O. J., Caunt, C. J., and Keyse, S. M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Oncogene
Publisher:Springer Nature
ISSN:0950-9232
ISSN (Online):1476-5594
Published Online:13 April 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Oncogene 41(): 2811-2823
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
174115CRUK Centre RenewalOwen SansomCancer Research UK (CRUK)C7932/A25142CS - Beatson Institute for Cancer Research
174328Precision-Panc: a dynamic therapeutic development platform for pancreatic cancerOwen SansomCancer Research UK (CRUK)C7932/A25233CS - Beatson Institute for Cancer Research