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

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Malignant tumor progression depends on the (transient) acquisition of invasive cellular traits, but we still do not fully understand the underlying regulatory mechanisms. TGFß signaling plays diverse roles during colorectal carcinoma (CRC) progression and may act as an early tumor suppressor or later control invasion and metastasis. In addition, TGFß critically influences the tumor microenvironment, e.g. by recruitment of cancer-associated fibroblasts (CAFs). A high fibroblast content is associated with poor tumor prognosis and CAFs may promote tumor growth directly or indirectly by causing immunosuppression. However, it is currently unknown, which specialized fibroblast populations are involved, and how their formation and plasticity is controlled. Zeb1 has been identified as key downstream factor of TGFβ and master regulator of epithelial-mesenchymal transition (EMT) in tumor cells. In addition, Zeb1 shows prominent expression in a subset of CAFs. Here, we have established tissue-specific knock-out and co-culture/transplantation models to address the role of Zeb1 in CAFs. Our preliminary results show that fibroblast-specific depletion of Zeb1 enhances primary tumor growth by attenuating a tumor-suppressive environment in a colitis-associated cancer model. Co-culture experiments using tumor organoids showed altered niche function and impaired plasticity of Zeb1 deficient fibroblasts. We will characterize the impact of stromal Zeb1 on the tumor microenvironment using invasive mouse models of colon cancer. Fibroblast subtypes and immune cell recruitment will be studied by single cell RNA sequencing. Organoid co-culture and transplantation models will be used for mechanistic dissection of the paracrine cell interactions. Subsequently we will use human CRC samples and clinical data sets to test whether modulation of ZEB1-dependent fibroblast plasticity may offer a therapeutic option.