Circumventing senescence is associated with stem cell properties and metformin sensitivity
Circumventing senescence is associated with stem cell properties and metformin sensitivity
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DOI：
10.1111/acel.12889
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发表时间：
2019-04-01
期刊：
影响因子：
7.8
通讯作者：
Ferbeyre, Gerardo
中科院分区：
文献类型：
--
作者：
Deschenes-Simard, Xavier;Parisotto, Maxime;Ferbeyre, Gerardo
大多数癌症发生在老年人身上，老年人也会积累衰老细胞。细胞衰老可以通过培养物连续传代过程中癌基因的表达或端粒缩短来实验诱导。在体内，几种癌症类型的前体病变会积累衰老细胞，这被认为代表了恶性进展的障碍以及对癌基因（癌基因毒性）异常激活生长信号通路的反应。在这里，我们试图定义与绕过致癌 RAS 诱导的衰老的细胞相关的基因表达变化。在胰腺导管腺癌 (PDAC) 中，致癌 KRAS 会诱发良性胰腺上皮内瘤变 (PanIN)，其表现出癌基因诱导的衰老特征。我们发现，绕过 PanIN 的衰老会导致恶性 PDAC 细胞，其特征是上皮间质转化、干细胞和线粒体的基因特征。用LPS处理的PanIN细胞以及在ERK信号传导减少后绕过Ras诱导的衰老的原代成纤维细胞和乳腺上皮细胞中也获得了类似的干细胞特性。有趣的是，二甲双胍（一种电子传递链复合物 I 的抑制剂）或 STAT3（一种线粒体功能和干性所需的蛋白质）的消耗会阻断细胞维持避免衰老并获得干细胞特性的作用。因此，我们的研究将癌前病变中衰老的旁路与分化丧失、干性特征的获得以及对线粒体功能的依赖增加联系起来。
Most cancers arise in old individuals, which also accumulate senescent cells. Cellular senescence can be experimentally induced by expression of oncogenes or telomere shortening during serial passage in culture. In vivo, precursor lesions of several cancer types accumulate senescent cells, which are thought to represent a barrier to malignant progression and a response to the aberrant activation of growth signaling pathways by oncogenes (oncogene toxicity). Here, we sought to define gene expression changes associated with cells that bypass senescence induced by oncogenic RAS. In the context of pancreatic ductal adenocarcinoma (PDAC), oncogenic KRAS induces benign pancreatic intraepithelial neoplasias (PanINs), which exhibit features of oncogene-induced senescence. We found that the bypass of senescence in PanINs leads to malignant PDAC cells characterized by gene signatures of epithelial-mesenchymal transition, stem cells, and mitochondria. Stem cell properties were similarly acquired in PanIN cells treated with LPS, and in primary fibroblasts and mammary epithelial cells that bypassed Ras-induced senescence after reduction of ERK signaling. Intriguingly, maintenance of cells that circumvented senescence and acquired stem cell properties was blocked by metformin, an inhibitor of complex I of the electron transport chain or depletion of STAT3, a protein required for mitochondrial functions and stemness. Thus, our studies link bypass of senescence in premalignant lesions to loss of differentiation, acquisition of stemness features, and increased reliance on mitochondrial functions.