TGF-β Tumor Suppression through a Lethal EMT.
TGF-β Tumor Suppression through a Lethal EMT.
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DOI：
10.1016/j.cell.2016.01.009
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发表时间：
2016-02-25
期刊：
影响因子：
64.5
通讯作者：
Massagué J
中科院分区：
文献类型：
--
作者：
David CJ;Huang YH;Chen M;Su J;Zou Y;Bardeesy N;Iacobuzio-Donahue CA;Massagué J
TGF-β信号传导可以是促肿瘤发生的或肿瘤抑制的。我们在胰腺导管腺癌（PDA）中研究了这种双重性，PDA与其他胃肠道癌症一样，表现出TGF-β介导物Smad 4的频繁失活。我们发现，TGF-β诱导上皮-间质转化（EMT），通常被认为是促肿瘤发生事件。然而，在TGF-β敏感的PDA细胞中，EMT通过将TGF-β诱导的Sox 4从肿瘤发生的执行者转化为凋亡的促进者而变得致命。这是细胞转录因子景观的EMT相关重塑的结果，包括胃肠谱系主调节因子Klf 5的抑制。Klf 5与Sox 4在肿瘤发生中协同作用并阻止Sox 4诱导的细胞凋亡。Smad 4是TGF-β诱导EMT所必需的，而Sox 4是TGF-β诱导EMT所必需的。因此，TGF-β诱导的Sox 4适合于支持祖细胞身份，而同时Smad 4依赖性EMT剥夺了Sox 4在肿瘤发生中的重要伴侣。我们的工作表明，TGF-β肿瘤抑制功能通过EMT介导的谱系特异性转录网络的破坏。
TGF-β signaling can be pro-tumorigenic or tumor suppressive. We investigated this duality in pancreatic ductal adenocarcinoma (PDA), which, with other gastrointestinal cancers, exhibits frequent inactivation of the TGF-β mediator Smad4. We show that TGF-β induces an epithelial-mesenchymal transition (EMT), generally considered a pro-tumorigenic event. However, in TGF-β sensitive PDA cells, EMT becomes lethal by converting TGF-β-induced Sox4 from an enforcer of tumorigenesis into a promoter of apoptosis. This is the result of an EMT-linked remodeling of the cellular transcription factor landscape, including the repression of the gastrointestinal lineage-master regulator Klf5. Klf5 cooperates with Sox4 in oncogenesis and prevents Sox4-induced apoptosis. Smad4 is required for EMT but dispensable for Sox4 induction by TGF-β. TGF-β-induced Sox4 is thus geared to bolster progenitor identity, while simultaneous Smad4-dependent EMT strips Sox4 of an essential partner in oncogenesis. Our work demonstrates that TGF-β tumor suppression functions through an EMT-mediated disruption of a lineage-specific transcriptional network.