Abstract：
MAP4K4 is a serine/threonine kinase of the STE20 family involved in the regulation of actin cytoskeleton dynamics and cell motility. It has been proposed as a target of angiogenesis and inhibitors show potential in cardioprotection. MAP4K4 also mediates cell invasion in vitro, is overexpressed in various types of cancer, and is associated with poor patient prognosis. Recently, MAP4K4 has been shown to be overexpressed in pancreatic cancer, but its role in tumour initiation, progression, and metastasis is unknown. Here, using the KrasG12D Trp53R172H Pdx1-Cre (KPC) mouse model of pancreatic ductal adenocarcinoma (PDAC), we show that deletion of Map4k4 drives tumour initiation and progression. Moreover, we report that the acceleration of tumour onset is also associated with an overactivation of ERK and AKT, two major downstream effectors of KRAS, in vitro and in vivo. In contrast to the accelerated tumour onset caused by loss of MAP4K4, we observed a reduction in metastatic burden with both the KPC model and in an intraperitoneal transplant assay indicating a major role of MAP4K4 in metastatic seeding. In summary, our study sheds light on the dichotomous role of MAP4K4 in the initiation of PDAC onset, progression, and metastatic dissemination. It also identifies MAP4K4 as a possible druggable target against pancreatic cancer spread, but with the caveat that targeting MAP4K4 might accelerate early tumorigenesis. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
摘要：
MAP4K4是参与调节肌动蛋白细胞骨架动力学和细胞运动的STE20家族的丝氨酸/苏氨酸激酶。它已被提出作为血管生成的靶标和抑制剂在心脏保护中显示出潜力。MAP4K4还在体外介导细胞侵袭，在各种类型的癌症中过度表达，并与患者预后不良有关。最近,MAP4K4已被证明在胰腺癌中过度表达，但是它在肿瘤启动中的作用，programming,和转移是未知的。这里,使用KrasG12DTrp53R172HPdx1-Cre（KPC）胰腺导管腺癌（PDAC）小鼠模型，我们显示Map4k4的缺失驱动肿瘤的开始和进展。此外，我们报道，肿瘤发病的加速也与ERK和AKT的过度激活有关，KRAS的两个主要下游效应，在体外和体内。与MAP4K4丢失引起的加速肿瘤发作相反，我们观察到KPC模型和腹膜内移植测定的转移负荷降低，表明MAP4K4在转移接种中具有重要作用。总之,我们的研究揭示了MAP4K4在PDAC发作开始中的二分法作用，programming,和转移性播散。它还将MAP4K4确定为针对胰腺癌扩散的可能的药物靶标，但需要注意的是，靶向MAP4K4可能会加速早期肿瘤发生。©2024作者由JohnWiley＆SonsLtd代表英国和爱尔兰病理学会出版的病理学杂志。
