胰腺导管腺癌（PDAC）是一种高度致命的恶性肿瘤，因为它通常在晚期才被诊断出来。信号转导器和转录激活剂 5 (STAT5) 是一种与多种癌症类型的进展有关的转录因子。然而，它在 KRAS 驱动的胰腺肿瘤发生中的作用仍不清楚。我们用 LSL-Kras G12D 进行了研究； Ptf1a-Cre ERT (KCERT) 小鼠或 LSL-KrasG12D； LSL-Trp53R172H ； Pdx1-Cre (KPC) 小鼠与条件性破坏 STAT5 或完全缺乏白细胞介素 (IL)-22 的小鼠进行杂交。通过给予雨蛙素在小鼠中诱导胰腺炎。在原位移植和患者来源的异种移植 PDAC 模型以及 KPC 小鼠中研究了 STAT5 对 PDAC 预防的药理学抑制作用。人 PDAC 样本中 STAT5 的表达和磷酸化高于对照样本，并且肿瘤细胞中高水平的 STAT5 相关预后较差。胰腺细胞中 STAT5 的缺失大大减少了 KRAS 突变以及胰腺炎引起的腺泡导管化生 (ADM) 和 PDAC 病变。从机制上讲，我们发现 STAT5 直接与 ADM 介质、肝细胞核因子 (HNF) 1β 和 HNF4α 的启动子结合。此外，STAT5 在 PDAC 进展过程中维持肿瘤细胞的能量代谢方面发挥着至关重要的作用。慢性炎症诱导的 IL-22 信号传导增强 KRAS 突变介导的 STAT5 磷酸化。 IL-22 信号传导的缺陷减缓了 PDAC 的进展并消除了 STAT5 激活。总的来说，我们的研究结果确定胰腺 STAT5 激活是致癌 KRAS 信号传导的关键下游效应子，对 ADM 启动和 PDAC 进展至关重要，突出了其潜在的治疗脆弱性。©作者（或其雇主）2024。根据 CC BY-NC 允许重复使用。禁止商业再利用。请参阅权利和权限。英国医学杂志出版。

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.We performed studies with LSL-Kras G12D; Ptf1a-Cre ERT (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.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) 1β and HNF4α. 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.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.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.