O'Sullivan, Rhianna Shannon; (2025) Functional Single-Cell Analysis of Epithelial-Stromal Signalling and Phenotypic Plasticity in Colorectal Cancer. Doctoral thesis (Ph.D), UCL (University College London).

Text Rhianna Shannon OSullivan - PhD Thesis - Corrected.pdf - Accepted Version Access restricted to UCL open access staff until 1 June 2026. Download (169MB)

Abstract

Colorectal cancer (CRC) is a major global health burden, causing over 900,000 deaths worldwide each year. While standard-of-care chemotherapy regimens can extend survival, many CRC patients suffer from chemoresistance, culminating in recurrence and progression of advanced metastatic disease, ultimately leading to mortality. CRC tumours are highly heterogeneous and are surrounded by a dense heterocellular tumour microenvironment (TME), which promotes tumour progression and hinders therapeutic efficacy. As the most abundant cell type within the stroma, cancer-associated fibroblasts (CAFs) can interact with tumour cells to promote cancer progression and chemoresistance, however, the exact mechanisms underlying this interaction are poorly understood. To this end, I performed functional single cell analysis of 10 CRC patient-derived organoids (PDOs) with and without CAFs to explore the intercellular signalling networks and phenotypic plasticity underlying CRC chemoresistance. Transcriptomic profiling of PDO-CAF co-cultures revealed the critical role of colonic stem cell (CSC) plasticity in CRC therapeutic response. I discovered that the proliferative CSC (proCSC) to revival CSC (revCSC) transdetermination axis is a master regulator of intrinsic chemosensitivity, alongside the crucial role of CAFs in polarising patient-specific PDOs towards chemoresistant revCSC fates. Furthermore, I demonstrated that extrinsic CRC epithelial plasticity is dictated by the cell-intrinsic transcriptome, underpinned by distinct transcriptional reprogramming, discrete TF-gene regulatory networks, and DACH1 expression. Collectively, these discoveries reveal fundamental mechanisms of both cell-intrinsic and extrinsic CRC chemoresistance. By understanding the regulators of stem cell plasticity in CRC, this work lays the foundation for new opportunities to identify rational, personalised therapeutic approaches to improve chemotherapeutic efficacy and patient outcomes.

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