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Oncogenic Ras/Src cooperativity in pancreatic neoplasia

机译：胰腺癌中的致癌性Ras / Src协同作用

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Pancreas cancer is one of the most lethal malignancies and is characterized by activating mutations of Kras, present in 95% of patients. More than 60% of pancreatic cancers also display increased c -Src activity, which is associated with poor prognosis. Although loss of tumor suppressor function (for example, p16, p53, Smad4) combined with oncogenic Kras signaling has been shown to accelerate pancreatic duct carcinogenesis, it is unclear whether elevated Src activity contributes to Kras-dependent tumorigenesis or is simply a biomarker of disease progression. Here, we demonstrate that in the context of oncogenic Kras, activation of c -Src through deletion of C-terminal Src kinase (CSK) results in the development of invasive pancreatic ductal adenocarcinoma (PDA) by 5鈥? weeks. In contrast, deletion of CSK alone fails to induce neoplasia, while oncogenic Kras expression yields PDA at low frequency after a latency of 12 months. Analysis of cell lines derived from Ras/Src-induced PDA's indicates that oncogenic Ras/Src cooperativity may lead to genomic instability, yet Ras/Src-driven tumor cells remain dependent on Src signaling and as such, Src inhibition suppresses growth of Ras/Src-driven tumors. These findings demonstrate that oncogenic Ras/Src cooperate to accelerate PDA onset and support further studies of Src-directed therapies in pancreatic cancer.
机译：胰腺癌是最致命的恶性肿瘤之一，其特征在于激活了95％的患者中存在的Kras突变。超过60％的胰腺癌还显示出增加的c -Src活性，这与不良的预后有关。尽管已经证实肿瘤抑制功能的丧失（例如，p16，p53，Smad4）与致癌性Kras信号的结合可加速胰腺导管癌变，但尚不清楚Src活性升高是否促成Kras依赖性肿瘤发生或仅仅是疾病的生物标志物进展。在这里，我们证明在致癌性Kras的背景下，通过删除C端Src激酶（CSK）激活c-Src导致5'？侵袭性胰腺导管腺癌（PDA）的发展。周。相比之下，仅CSK的缺失不能诱导瘤形成，而致癌性Kras表达在12个月的潜伏期后低频产生PDA。对源自Ras / Src诱导的PDA的细胞系的分析表明，致癌的Ras / Src协同作用可能导致基因组不稳定，但是Ras / Src驱动的肿瘤细胞仍然依赖于Src信号传导，因此，Src抑制抑制了Ras / Src的生长。驱动的肿瘤。这些发现表明，致癌性Ras / Src可协同促进PDA的发作，并支持胰腺癌中Src定向疗法的进一步研究。

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