TWEAK/Fn14 distinctly remodels the transcriptomic and epigenetic landscape in triple negative breast cancer to drive its progression

• Main Author: Sim, Nicholas Yang-U
• Other Authors: Li Yinghui
• Format: Thesis-Doctor of Philosophy
• Language: English
• Published: Nanyang Technological University 2023
• Subjects: Science::Biological sciences::Genetics; Science::Biological sciences::Molecular biology
• Online Access: https://hdl.handle.net/10356/169950
• Institution: Nanyang Technological University

Breast cancer is the most prevalent malignancy in women and one of the leading causes of cancer-related deaths globally. Of which, roughly 20% of cases are Triple Negative Breast Cancers (TNBC) which are highly aggressive and lack hormone receptors, rendering standard systemic therapy ineffective. Consequently, TNBCs account for a disproportionate number of breast cancer deaths compared to other breast cancer subtypes, highlighting an urgent need for novel TNBC targeted therapies. Recently, the Fibroblast Growth Factor-Inducible 14 (Fn14) receptor was found to be overexpressed in Estrogen Receptor (ER) negative breast cancers and associated with worse prognosis, making it an attractive target for therapy. However, our understanding of the Fn14 signalling mechanism and its role in breast cancer is very limited. In this study, we first characterised the functional roles of Fn14 activation through its ligand Tumour Necrosis Factor-like Weak Inducer of Apoptosis (TWEAK) between TNBCs and ER+ breast cancers. Here, we demonstrate that TWEAK/Fn14 signalling specifically drives cancer cell proliferation and invasion in TNBCs. To elucidate the TWEAK/Fn14 signalling mechanism of action, we took a multi-omics approach. Through which, we show that TWEAK/Fn14 signalling regulates TNBC-specific transcriptomic and enhancer signatures which are associated with enhanced cell proliferation and migration. Subsequently, we confirmed the correlation between the transcriptomic, epigenetic and phenotypic changes observed through Acetylation of Histone H3 at lysine 27 (H3K27ac) HiChIP. This revealed a significant increase in TWEAK/Fn14-driven chromatin looping between upregulated enhancers and promoters of upregulated genes in TNBC. We then demonstrate the functionality of these loops, through CRISPR-mediated perturbation of a TNBC-specific superenhancer (SE). Taken together, our study not only demonstrates a comprehensive mechanism linking the epigenetic and transcriptomic alterations driven by TWEAK/Fn14 signalling through increased chromatin looping which drives TNBC progression, but also highlights the immense therapeutic potential of exploiting Fn14 in TNBC.