Pancreatic STAT5 activation promotes KrasG12D-induced and inflammation-induced acinar-to-ductal metaplasia and pancreatic cancer

Menée à l'aide de xénogreffes sur des modèles murins d'adénocarcinomes canalaires du pancréas, cette étude met en évidence un mécanisme par lequel l'activation de STAT5 (un transducteur de signal et activateur de transcription), via la signalisation de l'interleukine IL-22 induite par l'inflammation chronique et la signalisation oncogène de KRAS G12D, favorise la métaplasie acino-canalaire et le développement tumoral

Résumé en anglais

Objective : Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy because it is often diagnosed at a late-stage. Signal transducer and activator of transcription 5 (STAT5) is a transcription factor implicated in the progression of various cancer types. However, its role in KRAS-driven pancreatic tumourigenesis remains unclear.

Design : We performed studies with LSL-KrasG12D; Ptf1a-CreERT (KCERT) mice or LSL-KrasG12D; LSL-Trp53R172H; Pdx1-Cre (KPC) mice crossed with conditional disruption of STAT5 or completed deficiency interleukin (IL)-22. Pancreatitis was induced in mice by administration of cerulein. Pharmacological inhibition of STAT5 on PDAC prevention was studied in the orthotopic transplantation and patient-derived xenografts PDAC model, and KPC mice.

Results : The expression and phosphorylation of STAT5 were higher in human PDAC samples than control samples and high levels of STAT5 in tumour cells were associated with a poorer prognosis. The loss of STAT5 in pancreatic cells substantially reduces the KRAS mutation and pancreatitis-derived acinar-to-ductal metaplasia (ADM) and PDAC lesions. Mechanistically, we discovered that STAT5 binds directly to the promoters of ADM mediators, hepatocyte nuclear factor (HNF) 1