In this thesis, we aimed to better understand the underlying mechanisms involved in TNBC progression and metastasis formation and discover new targets to reduce breast cancer related deaths. We... Show moreIn this thesis, we aimed to better understand the underlying mechanisms involved in TNBC progression and metastasis formation and discover new targets to reduce breast cancer related deaths. We performed an imaging-based RNAi phenotypic cell migration screen in two highly motile TNBC cancer cell lines to provide a repository of signaling determinants that functionally drive TNBC cell motility. Interestingly, two modulators essential for cancer cell migration were known to be involved in RNA splicing, making us decide to focus on the role of RNA splicing in breast cancer progression. We next summarized the current knowledge about splicing factors in breast cancer development and progression and identified co-regulated splicing factors that were associated with aggressive breast cancer phenotypes and metastasis formation that was not only restricted to breast cancer, increasing the global understanding of the role of the spliceosome in cancer development and progression. Moreover, the role of splicing factors in two major processes in cancer progression, cell migration and proliferation, was examined. Finally, using RNA sequencing, we systematically compared the transcriptomes of 14 breast cancer cell lines cultured both in 2D and 3D conditions to unravel the reprogramming that is associated with the invasive phenotype of basal B TNBC. Show less
My PhD studies focused on understanding the role of macrophages, a type of immune cells which are abundantly present in several tumor types, in breast cancer progression and therapy response.In the... Show moreMy PhD studies focused on understanding the role of macrophages, a type of immune cells which are abundantly present in several tumor types, in breast cancer progression and therapy response.In the first part of my thesis, I describe how macrophages can acquire different functional characteristics in different types of breast cancer. Next, I focused on understanding the interplay between macrophages and cancer therapies. In particular, I revealed that macrophages counteract the efficacy of conventional chemotherapy drugs. I showed that eliminating macrophages with an antibody that targets CSF-1 receptor (CSF-1R) enhances the anti-cancer efficacy of platinum-based chemotherapeutic agents in breast cancer. I mechanistically discovered that CSF-1R inhibition stimulates intratumoral type I interferon signaling which is essential for the therapeutic synergy between cisplatin and CSF-1R blockade. I also uncovered that further elimination of immunosuppressive neutrophils, another type of immune cells, was required to engage an efficacious anti-tumor immunity. Show less
This thesis is about clinical quality audits, used to measure and improve the quality of health care; focusing on the quality of breast cancer care (see: the NBCA) and on the quality of breast... Show moreThis thesis is about clinical quality audits, used to measure and improve the quality of health care; focusing on the quality of breast cancer care (see: the NBCA) and on the quality of breast implant surgery (see: the DBIR) in the Netherlands. Show less
