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

Andrew M. Kidger, Mark K. Saville, Linda K. Rushworth, Jane Davidson, Julia Stellzig, Motoharu Ono, Ludwig A. Kuebelsbeck, Klaus Peter Janssen, Bernhard Holzmann, Jennifer P. Morton, Owen J. Sansom, Christopher J. Caunt, Stephen M. Keyse

    Research output: Contribution to journalArticlepeer-review

    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 languageEnglish
    Pages (from-to)2811-2823
    Number of pages13
    JournalOncogene
    Volume41
    Issue number20
    Early online date13 Apr 2022
    DOIs
    Publication statusPublished - 13 May 2022

    ASJC Scopus subject areas

    • Molecular Biology
    • Genetics
    • Cancer Research

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