Maddalena, Maurizio (2025) Unveiling the Role of Neutrophil Extracellular Traps in Tumour Progression. [Tesi di dottorato]

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Abstract

The dynamic interactions between cancer cells and tumor micronvironment can significantly affect tumor growth, metastatic spread and response to therapy. A growing body of evidences indicates that tumour microenvironment is a complex ecosystem consisting of a heterogeneous collection of infiltrating and resident host cells, secreted factors, and extracellular matrix. Among the infiltrating cells, tumor-associated neutrophils (TANs) are characterized by their high diversity and plasticity and may assume both a pro and anti-tumor phenotype. Moreover, activated neutrophils can release neutrophil extracellular traps (NETs) that were recently reported to favour tumor growth and progression. The primary function of NETs is to kill and inactivate pathogens. However, they were found to be present in primary tumors and in the blood of cancer patients and previous studies indicated that NETs can modulate different steps of the metastatic cascade. The aim of the present study was to characterize the functions of NETs in cancer progression, with a particular focus on their ability to promote cancer cell adhesion, induce epithelial-mesenchymal transition (EMT) and enhance cell migration. The study also explored the pathways behind the NET-dependent modulation of these processes. Our study showed that a NET layer can serve as an adhesion substrate for a panel of epithelial cancer cells including HCC827 and H1993 non-small cell lung cancer cells, MCF-7 breast cancer cells and HT1080 human fibrosarcoma cells. All cancer cell lines showed a higher adhesion to NET-coated plates as compared to that observed in uncoated plates. Furthermore, we simultaneously tested the ability of CCDC25 receptor and α5β1 integrin to mediate cell adhesion to NETs, based on the reported observations that CCDC25 interacts with DNA and α5β1 integrin binds to fibronectin within the structure of NETs. We found that they were equally effective in mediating cell adhesion to NETs. The most relevant finding of our study was the demonstration that the prolonged exposure of certain cancer cell lines to NETs can activate the EMT program driving a sequence of events leading to enhanced cell migration and loss of the epithelial phenotype. We showed indeed that the activation of the EMT program is mediated by NOTCH 1 upregulation followed by an increase of its activated cleaved form that in turn led to the overexpression of transcription factors such as Snail, Slug, Zeb 1 and Twist orchestrating the EMT program. These findings were confirmed by the loss of the epithelial phenotype since levels of the oncogene driver EGFR and its phosphorylated form were decreased and downstream signaling mediators were downregulated. The acquisition of a mesenchymal phenotype upon exposure to NETs was associated with an enhanced migratory ability of cancer cells. In conclusion, our study showed that cancer cells can bind to NETs and that the prolonged exposure to NETs can induce the upregulation and activation of Notch 1 that in turn can drive the EMT thus enhancing the migratory and invasiveness of cancer cells.

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