The role of the EMT-inducer Zeb1 in the invasive tumor stroma during colon cancer progression

EMT诱导剂Zeb1在结肠癌进展过程中侵袭性肿瘤基质中的作用

• 批准号: 319467242
• 负责人: Professor Dr. Thomas Brabletz
• 金额: --
• 依托单位: Georg-Speyer-Haus, Institut für Tumorbiologie und experimentelle Therapie
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/319467242?language=en
• 关键词: role; EMT; inducer; Zeb1; invasive

Metastasis depends on the (transient) acquisition of invasive cellular traits, but we still do not fully understand the underlying (epi-)genetic changes. TGFb-signaling can play both activating and repressing roles in colorectal carcinomas (CRC) progression. During the early stages of tumorigenesis, its role as a tumor suppressor is due to powerful inhibition of growth of epithelial cells. However as tumors evolve, TGFb-induced epithelial-mesenchymal transition (EMT) contributes in malignant progression, e.g. by induction of the transcriptional master regulator Zeb1 (1). Most recently it has been shown that a TGFb profile in stromal fibroblasts is predictive for aggressive disease (2). TGFb-activated stroma is sufficient to impose a pro-metastatic phenotype on CRC cells, but it is not known which stromal factors mediate invasion nor which oncogenic lesions predispose to a metastatic phenotype. We have shown that Zeb1 can regulate expression of soluble factors such as cytokines and is highly upregulated in the invasive stroma of aggressive cancers. Here we want to investigate the role of Zeb1 in the stromal crosstalk using tissue-specific knock-out models and co-culture/transplantation of tumor organoids.

转移取决于（瞬态）侵入性细胞性状的（瞬态），但我们仍然不完全理解基本的（表 - ）遗传变化。 TGFB信号可以在结直肠癌（CRC）进展中扮演激活和抑制角色。在肿瘤发生的早期阶段，其作为肿瘤抑制剂的作用是由于对上皮细胞生长的强大抑制作用。然而，随着肿瘤的发展，TGFB诱导的上皮间质转变（EMT）有助于恶性进展，例如通过诱导转录主调节ZEB1（1）。最近，已经表明，基质成纤维细胞中的TGFB特征可以预测侵袭性疾病（2）。 TGFB激活的基质足以在CRC细胞上施加促异常表型，但尚不清楚哪些基质因子介导侵袭，也不知道哪些致癌性病变易于转移性表型。我们已经表明，Zeb1可以调节可溶性因子（例如细胞因子）的表达，并且在侵袭性癌症的侵入性基质中被高度上调。在这里，我们要使用组织特异性的基因敲除模型和肿瘤器官的共培养/移植来研究Zeb1在基质串扰中的作用。