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.
Original language | English |
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Pages (from-to) | 2811-2823 |
Number of pages | 13 |
Journal | Oncogene |
Volume | 41 |
Issue number | 20 |
Early online date | 13 Apr 2022 |
DOIs | |
Publication status | Published - 13 May 2022 |
Bibliographical note
Funding Information:We would like to thank the staff of the Biological Resources Unit (Ninewells Hospital) and The Biological Services Unit (CRUK Beatson Institute, Glasgow) for animal husbandry and technical assistance. Tayside Tissue Bank (Mairi Lennie and Sharon King) for tissue sectioning and slide scanning. Richard Odle (Babraham Institute, Cambridge) for IHC scoring. Catherine Winchester (CRUK Beatson Institute, Glasgow) for critical reading of the manuscript, Ian Rosewell, Linda Groom, David Williams and Susanne Van Schelven for technical assistance during the early stages of this project. 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). We dedicate this manuscript to the memory of our friend and colleague CJC.
Funding Information:
We would like to thank the staff of the Biological Resources Unit (Ninewells Hospital) and The Biological Services Unit (CRUK Beatson Institute, Glasgow) for animal husbandry and technical assistance. Tayside Tissue Bank (Mairi Lennie and Sharon King) for tissue sectioning and slide scanning. Richard Odle (Babraham Institute, Cambridge) for IHC scoring. Catherine Winchester (CRUK Beatson Institute, Glasgow) for critical reading of the manuscript, Ian Rosewell, Linda Groom, David Williams and Susanne Van Schelven for technical assistance during the early stages of this project. 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). We dedicate this manuscript to the memory of our friend and colleague CJC.
ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Cancer Research