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Aberrant induction of a mesenchymal/stem-cell program engages senescence in normal mammary epithelial cells
Molecular Cancer Research ( IF 4.1 ) Pub Date : 2020-12-22 , DOI: 10.1158/1541-7786.mcr-19-1181
Benjamin L Bryson 1, 2 , Ilaria Tamagno 1, 2 , Sarah E Taylor 1 , Neetha Parameswaran 1 , Noah M Chernosky 1, 2 , Nikhila Balasubramaniam 1 , Mark W Jackson 1, 2
Affiliation  

Though frequently associated with tumor progression, inflammatory cytokines initially restrain transformation by inducing senescence, a key tumor-suppressive barrier. Here, we demonstrate that the inflammatory cytokine Oncostatin M (OSM) activates a mesenchymal/stem cell (SC) program that engages cytokine-induced senescence (CIS) in normal human epithelial cells. CIS is driven by Snail induction and requires cooperation between STAT3 and the TGF-β effector SMAD3. Importantly, as cells escape CIS, they retain the mesenchymal/SC program and are thereby bestowed with a set of cancer SC (CSC) traits. Of therapeutic importance, cells that escape CIS can be induced back into senescence by CDK4/6 inhibition, confirming that the mechanisms allowing cells to escape senescence are targetable and reversible. Moreover, by combining CDK4/6 inhibition with a senolytic therapy, mesenchymal/CSC can be efficiently killed. Our studies provide insight into how the CIS barriers that prevent tumorigenesis can be exploited as potential therapies for highly aggressive cancers. Implications: These studies reveal how a normal cell's arduous escape from senescence can bestow aggressive features early in the transformation process, and how this persistent mesenchymal/stem-cell program can create a novel potential targetability following tumor development.

中文翻译:

间充质/干细胞程序的异常诱导参与正常乳腺上皮细胞的衰老

虽然经常与肿瘤进展相关,但炎性细胞因子最初通过诱导衰老来抑制转化,这是一种关键的肿瘤抑制屏障。在这里,我们证明炎症细胞因子制瘤素 M (OSM) 激活间充质/干细胞 (SC) 程序,该程序在正常人上皮细胞中参与细胞因子诱导的衰老 (CIS)。CIS 由 Snail 诱导驱动,需要 STAT3 和 TGF-β 效应子 SMAD3 之间的合作。重要的是,随着细胞逃离 CIS,它们保留了间充质/SC 程序,因此被赋予了一组癌症 SC (CSC) 特征。具有治疗意义的,逃避 CIS 的细胞可以通过抑制 CDK4/6 被诱导回衰老,这证实了允许细胞逃避衰老的机制是可靶向的和可逆的。而且,通过将 CDK4/6 抑制与衰老治疗相结合,可以有效地杀死间充质/CSC。我们的研究提供了有关如何将阻止肿瘤发生的 CIS 屏障用作高侵袭性癌症的潜在疗法的见解。启示:这些研究揭示了正常细胞如何艰难地摆脱衰老,从而在转化过程的早期赋予攻击性特征,以及这种持续的间充质/干细胞程序如何在肿瘤发展后产生新的潜在靶向性。
更新日期:2020-12-22
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