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

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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.