Myeloid ZEB1 in the gastrointestinal tumor and metastatic microenvironment

Document Type
Doctoral Thesis
Granting Institution
Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Naturwissenschaftliche Fakultät
Issue Date
Fuchs, Kathrin

Cancer is one of the leading causes of morbidity worldwide. Colorectal (CRC) and pancreatic (PDAC) cancer will account for almost 20% of all expected cancer deaths in 2023. While cancer research mainly focused on the malignant tumor cells for many years, the critical impact of the tumor microenvironment (TME) on tumor progression has recently come into focus. In particular, tumor associated macrophages (TAMs) in the TME play a dual role in influencing clinical outcome of cancer patients, depending on their polarization towards tumor suppressive or supportive subtypes. The transcription factor ZEB1 conveys plasticity to numerous cell types, for example the epithelial-to-mesenchymal transition in tumor cells, which fosters malignant progression. Interestingly, ZEB1 is also present in stromal cells of TME. In this study, we therefore sought to investigate how plasticity factor ZEB1 can alter TAM polarization and functions and thereby affect gastrointestinal tumor development and metastatic colonization. Based on clinical data, we demonstrate the expression of ZEB1 in TAMs in primary tumors and metastases. Employment of a mouse model with conditional homozygous knockout of myeloid Zeb1 (ZEB1LysMDel) revealed no evident impact of myeloid ZEB1 on organ development, tissue and immune homeostasis in mice. In contrast, myeloid ZEB1 depletion resulted in increased tumor growth and tumorgenicity of subcutaneous syngeneic allografts of CRC cell line CMT 93. These results were partially reproduced in CRC cell line MC 38 and PDAC cell line KPCz661. Moreover, metastatic lung colonization of KPCz661 was also considerably enhanced in ZEB1LysMDel compared to control mice. Surprisingly, in vitro characterization of macrophages derived from ZEB1LysMDel mice did not reveal ZEB1 as a master regulator of macrophage polarization transcription, but rather as fine tuner of specific macrophage effectors. Remarkably, we provide evidence that the secretion of cytokines CCL2 and CCL22 by ZEB1 proficient macrophages may be responsible for macrophage-mediated chemotaxis of cytotoxic T cells into the TME. ZEB1 deficient macrophages were incapable of recruiting sufficient cytotoxic T cells into the TME, resulting in diminished tumor cell apoptosis and subsequently increased tumor or metastatic colony burden. Collectively, our data provide evidence for a novel and unanticipated tumor suppressive function of ZEB1 in TAMs by chemokine mediated cytotoxic T cell recruitment. This study reinforces the importance of the complex interactions in the TME and their influence on cancer biology.

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