Malignant transformation entails important changes in the control of cell proliferation through the rewiring of selected signaling pathways. Cancer cells then become very dependent on the proper function of those pathways, and their inhibition offers therapeutic opportunities. Here we identify the stress kinase p38α as a nononcogenic signaling molecule that enables the progression of KrasG12V-driven lung cancer. We demonstrate in vivo that, despite acting as a tumor suppressor in healthy alveolar progenitor cells, p38α contributes to the proliferation and malignization of lung cancer epithelial cells. We show that high expression levels of p38α correlate with poor survival in lung adenocarcinoma patients, and that genetic or chemical inhibition of p38α halts tumor growth in lung cancer mouse models. Moreover, we reveal a lung cancer epithelial cell-autonomous function for p38α promoting the expression of TIMP-1, which in turn stimulates cell proliferation in an autocrine manner. Altogether, our results suggest that epithelial p38α promotes KrasG12V-driven lung cancer progression via maintenance of cellular self-growth stimulatory signals.

中文翻译：

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KRAS驱动的肺肿瘤进展中对上皮p38α的需求。

恶性转化需要通过重新选择信号通路重新控制细胞增殖。然后，癌细胞变得非常依赖那些途径的正常功能，并且它们的抑制作用提供了治疗机会。在这里，我们确定应激激酶p38α为非致癌信号分子，能够使KrasG12V驱动的肺癌进展。我们在体内证明，尽管在健康的肺泡祖细胞中起着抑癌作用，但p38α却有助于肺癌上皮细胞的增殖和恶变。我们显示p38α的高表达水平与肺腺癌患者的不良生存相关，并且p38α的遗传或化学抑制作用可阻止肺癌小鼠模型中的肿瘤生长。此外，我们揭示了p38α促进TIMP-1表达的肺癌上皮细胞自主功能，进而以自分泌方式刺激细胞增殖。总之，我们的结果表明，上皮细胞p38α通过维持细胞自身生长刺激信号来促进KrasG12V驱动的肺癌进展。