ID1 Mediates Escape from TGFβ Tumor Suppression in Pancreatic Cancer
ID1 Mediates Escape from TGFβ Tumor Suppression in Pancreatic Cancer
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DOI：
10.1158/2159-8290.cd-19-0529
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发表时间：
2020-01-01
期刊：
影响因子：
28.2
通讯作者：
Massague, Joan
中科院分区：
文献类型：
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作者：
Huang, Yun-Han;Hu, Jing;Massague, Joan
TGF β是胰腺导管腺癌（PDA）中重要的肿瘤抑制因子，但仅在一半的PDA病例中发生TGF β途径组分的失活。TGF β与致癌RAS信号传导合作以触发癌前胰腺上皮祖细胞中的上皮向间质转化（EMT），这与由于SOX 4和KLF 5转录因子的不平衡引起的细胞凋亡偶联。我们报告说，PDAs的发展与TGF β通路完整避免这种凋亡作用通过101。101家族成员在PDA祖细胞中表达，并编码PDA共有的一组核心转录调节因子的组分。PDA进展选择对抗TGF β介导的101抑制。101的持续表达使EMT与PDA祖细胞中的细胞凋亡解偶联。AKT信号传导和与低频遗传事件相关的机制聚集在101上，以保持其在PDA中的表达。我们的研究结果确定ID1作为一个关键的节点和潜在的治疗靶点在PDA.SIGNIFICANCE：一半的PDAs逃脱TGF β诱导的肿瘤抑制，而不灭活TGF β通路。我们报道了101在PDA中的表达被选择，并且ID1将TGF β诱导的EMT与细胞凋亡解偶联。因此，101成为PDA中的关键调节节点和感兴趣的靶标。
TGF beta is an important tumor suppressor in pancreatic ductal adenocarcinoma (PDA), yet inactivation of TGF beta pathway components occurs in only half of PDA cases. TGF beta cooperates with oncogenic RAS signaling to trigger epithelial-to-mesenchymal transition (EMT) in premalignant pancreatic epithelial progenitors, which is coupled to apoptosis owing to an imbalance of SOX4 and KLF5 transcription factors. We report that PDAs that develop with the TGF beta pathway intact avert this apoptotic effect via 101. 101 family members are expressed in PDA progenitor cells and encode components of a set of core transcriptional regulators shared by PDAs. PDA progression selects against TGF beta-mediated repression of 101. The sustained expression of 101 uncouples EMT from apoptosis in PDA progenitors. AKT signaling and mechanisms linked to low-frequency genetic events converge on 101 to preserve its expression in PDA. Our results identify ID1 as a crucial node and potential therapeutic target in PDA.SIGNIFICANCE: Half of PDAs escape TGF beta-induced tumor suppression without inactivating the TGF beta pathway. We report that 101 expression is selected for in PDAs and that ID1 uncouples TGF beta -induced EMT from apoptosis. 101 thus emerges as a crucial regulatory node and a target of interest in PDA.