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Development of patient-derived models to discover therapeutic strategies that target the breast tumour microenvironment

Li, Rui
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Identifiers
https://hdl.handle.net/10379/18962
 https://doi.org/10.13025/29756
Publication Date
2025-06-18
Keywords
Breast cancer, Tumour microenvironment, Cancer associated fibroblast, Patient-derived model, Wilms Tumour 1, medicine, surgery
Type
doctoral thesis
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Abstract
The intricacy of cellular and acellular components within tumours contributes to significant variation within the tumour microenvironment (TME) as well as the response to anticancer treatment. Heterogeneity and spatial tumour-stromal interactions, including cancer associated fibroblasts (CAFs), endothelial cells and tissue‐infiltrating immune cells, play significant roles in cancer progression and treatment response. Many conventional treatments including chemotherapy and targeted therapies target cancer cells, this approach can be further refined to target pro-tumourigenic stromal cells and tumour-stromal interactions within the TME. In this study, we have developed patient-derived models (PDMs) to model these complexities at the level of the individual patient with the aim of using these unique PDMs to discover innovative strategies to treat breast cancer. In the first part of this study (Chapter Three) we use two‐dimensional (2D) and three‐dimensional (3D) PDMs to screen a natural compound library to discover anti-tumourigenic compounds. We are able to use these unique PDMs, that incorporate the cellular interactions that take place within the TME, to unravel drug-TME interactions, target identification, and improved efficacy of therapies. This study provides the basis for the integration of autologous PDMs into predictive models for a personalised medicine approach. In the second part of this study (Chapter Four) we use these PDMs to explore the therapeutic benefit of targeting Wilms Tumour 1 (WT-1)+ CAFs within the tumour immune microenvironment. We describe the molecular mechanisms by which CAF-derived WT-1 promotes tumour growth and immune evasion, and discover therapeutic strategies that inhibit WT-1 within the TME thereby enhancing anti-tumour immunity. This study highlights the importance of PDMs in precision medicine and drug screening, providing a valuable platform for the interplay between the TME and therapeutic responses for breast cancer. The identification of novel therapeutic targets such as WT-1 and the development of natural products as lead anti-cancer compounds represent significant advancements toward personalised and effective breast cancer treatments.
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University of Galway
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CC BY-NC-ND
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University of Galway Theses (PhD Theses)