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

• Published in: Oncogene Vol. 41; no. 20; pp. 2811 - 2823
• Main Authors: Kidger, Andrew M., Saville, Mark K., Rushworth, Linda K., Davidson, Jane, Stellzig, Julia, Ono, Motoharu, Kuebelsbeck, Ludwig A., Janssen, Klaus-Peter, Holzmann, Bernhard, Morton, Jennifer P., Sansom, Owen J., Caunt, Christopher J., Keyse, Stephen M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.05.2022; Nature Publishing Group
• Subjects: 13; 13/51; 14; 42; 42/41; 631/67/395; 64; 64/60; 692/53/2423; 82; 82/29; 96; 96/106; Adenocarcinoma; Aging; Animal models; Animals; Apoptosis; Atrophy; Atrophy - pathology; Carcinogenesis; Carcinogenesis - genetics; Carcinogenesis - pathology; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - pathology; Cell Biology; Dual Specificity Phosphatase 6 - genetics; Dual-Specificity Phosphatases - genetics; Extracellular signal-regulated kinase; Human Genetics; Hyperplasia; Internal Medicine; MAP kinase; Medicine; Medicine & Public Health; Metaplasia; Metastases; Mice; Oncology; Pancreas - pathology; Pancreatic cancer; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Phosphatase; Proto-Oncogene Proteins p21(ras) - genetics; Tumors; Weight Loss
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-022-02302-0

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 KRAS G12D -driven pancreatic cancer. By 56-days, loss of either DUSP5 or DUSP6 causes a significant increase in KRAS G12D -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, Dusp 6 −/− 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 KRAS G12D 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.