| First Author | Lin Y | Year | 2024 |
| Journal | Gut | Volume | 73 |
| Issue | 11 | Pages | 1831-1843 |
| PubMed ID | 38955401 | Mgi Jnum | J:361186 |
| Mgi Id | MGI:7856544 | Doi | 10.1136/gutjnl-2024-332225 |
| Citation | Lin Y, et al. (2024) Pancreatic STAT5 activation promotes Kras(G12D)-induced and inflammation-induced acinar-to-ductal metaplasia and pancreatic cancer. Gut 73(11):1831-1843 |
| abstractText | 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-Kras (G12D); Ptf1a-Cre (ERT) (KC(ERT)) mice or LSL-Kras(G12D); LSL-Trp53(R172H) ; 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) 1beta and HNF4alpha. Furthermore, STAT5 plays a crucial role in maintaining energy metabolism in tumour cells during PDAC progression. IL-22 signalling induced by chronic inflammation enhances KRAS-mutant-mediated STAT5 phosphorylation. Deficiency of IL-22 signalling slowed the progression of PDAC and ablated STAT5 activation. CONCLUSION: Collectively, our findings identified pancreatic STAT5 activation as a key downstream effector of oncogenic KRAS signalling that is critical for ADM initiation and PDAC progression, highlighting its potential therapeutic vulnerability. |
