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

转移依赖于侵袭性细胞特征的（瞬时）获得，但我们仍然不完全了解潜在的（外）遗传变化。tgfb信号在结直肠癌（CRC）的发展过程中发挥激活和抑制作用。在肿瘤发生的早期阶段，它作为肿瘤抑制因子的作用是由于对上皮细胞的生长有强大的抑制作用。然而，随着肿瘤的发展，tgfb诱导的上皮-间质转化（EMT）有助于恶性进展，例如通过诱导转录主调控因子Zeb1(1)。最近有研究表明，间质成纤维细胞中的TGFb谱可预测侵袭性疾病(2)。tgfb激活的基质足以对CRC细胞施加前转移表型，但尚不清楚哪些基质因子介导侵袭，也不知道哪些致癌病变易导致转移表型。我们已经证明，Zeb1可以调节可溶性因子如细胞因子的表达，并且在侵袭性癌症的侵袭性基质中高度上调。在这里，我们想通过组织特异性敲除模型和肿瘤类器官共培养/移植来研究Zeb1在间质串扰中的作用。

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.