TGFβ is an important tumor suppressor in pancreatic ductal adenocarcinoma (PDA), yet inactivation of TGFβ pathway components occurs in only half of PDA cases. TGFβ 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 TGFβ pathway intact avert this apoptotic effect via ID1. ID1 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 TGFβ-mediated repression of ID1. The sustained expression of ID1 uncouples EMT from apoptosis in PDA progenitors. AKT signaling and mechanisms linked to low-frequency genetic events converge on ID1 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 TGFβ-induced tumor suppression without inactivating the TGFβ pathway. We report that ID1 expression is selected for in PDAs and that ID1 uncouples TGFβ-induced EMT from apoptosis. ID1 thus emerges as a crucial regulatory node and a target of interest in PDA.This article is highlighted in the In This Issue feature, p. 1.

中文翻译：

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ID1 介导胰腺癌中逃避 TGFβ 肿瘤抑制。


TGFβ 是胰腺导管腺癌 (PDA) 中重要的肿瘤抑制因子，但 TGFβ 通路成分失活仅发生在一半的 PDA 病例中。 TGFβ 与致癌 RAS 信号传导相配合，触发癌前胰腺上皮祖细胞的上皮间质转化 (EMT)，由于 SOX4 和 KLF5 转录因子的不平衡，EMT 与细胞凋亡相关。我们报告说，在 TGFβ 通路完整的情况下发育的 PDA 通过 ID1 避免了这种凋亡效应。 ID1 家族成员在 PDA 祖细胞中表达，并编码 PDA 共享的一组核心转录调节因子的组件。 PDA 进展选择对抗 TGFβ 介导的 ID1 抑制。 ID1 的持续表达使 PDA 祖细胞中的 EMT 与细胞凋亡解偶联。与低频遗传事件相关的 AKT 信号传导和机制汇聚在 ID1 上，以保留其在 PDA 中的表达。我们的结果将 ID1 确定为 PDA 的关键节点和潜在治疗靶点。意义：一半的 PDA 逃脱了 TGFβ 诱导的肿瘤抑制，而没有使 TGFβ 通路失活。我们报告说，PDA 中选择了 ID1 表达，并且 ID1 将 TGFβ 诱导的 EMT 与细胞凋亡解偶联。因此，ID1 成为 PDA 中的一个关键监管节点和感兴趣的目标。本文在本期特稿第 14 页中得到了重点介绍。 1.