Biology subjects

O'Sullivan, R.

Publications and source records attributed to O'Sullivan, R..

3 recordsLinked to original sources

bioRxiv2026

Epithelial Stem Cell Fate Determines Chemoradiotherapy Response in Rectal Cancer

Rectal cancers are often treated with neoadjuvant chemoradiotherapy (CRT), yet 85% of patients do not achieve a pathological complete response. To identify the molecular determinants of CRT response, we profiled the single-cell signalling, DNA-damage, cell-cycle, apoptotic, and cell-fate responses of 2,769 patient-derived organoid cultures treated with CRT, cancer-associated fibroblasts (CAFs), and signal-rewiring agents. We find that CRT response is determined by stem cell-fate. CRT triggers comparable DNA-damage in isogenic proliferative (proCSC) and revival (revCSC) colonic stem cells, but proCSC retain damage and die whereas revCSC resolve damage and persist. Both CRT and CAFs drive proCSC to a common treatment-resistant revCSC fate and high revCSC predicts worse survival in patients. Pharmacologically constraining stem-cell plasticity increases CRT sensitivity, and Spatial Perturbation of ARrayed Tumour Assembloids (SPARTA) confirms YAP/TEAD inhibition improves chemotherapy responses in human stromal-tumour models. These results suggest that cancer cell-fate, not genotoxic damage itself, ultimately governs response to standard-of-care chemoradiotherapy. HIGHLIGHTSO_LIRectal cancer stem cell-fate determines chemoradiotherapy-induced apoptosis C_LIO_LIproCSCs retain DNA-damage and die, whereas revCSCs repair damage and persist C_LIO_LICAFs and chemoradiotherapy converge on a common chemo-radioresistant revCSC state C_LIO_LISPARTA reveals TEAD inhibition blocks DNA-repair persisters in stromal assembloids C_LI

cancer biology↗

bioRxiv2025

Ephrin inhibition disrupts stromal-cancer crosstalk and reduces metastasis in pancreatic cancer

Cancer associated fibroblasts (CAFs) are critical drivers of disease progression and metastasis within the pancreatic tumour microenvironment. Using a 3D spheroid model of CAF-led invasion, we identified complementary expression of ephrin family receptors (EPHB2) and ligands (EPHRINB2) between cancer cells and CAFs, implicating this bidirectional signalling family in tumour progression. Through pancreatic stellate cell-derived CAFs isolated from genetically modified mouse models, where EphrinB was either lacking or modified by a gain-of-function mutation, we identified both forward and reverse signalling to be required for invasion. In a syngeneic murine orthotopic model of pancreatic cancer, we show that first-in-class tetramerisation inhibitors of Eph/Ephrin interactions can reduce local invasion in primary tumours, and significantly decrease metastatic tumour spread across multiple organ sites. Our data highlight Ephrin signalling as a critical nexus for CAF-cancer crosstalk and establish a foundation for the clinical development of targeted EPH-EPHRIN inhibitors to counter metastatic invasion.

cancer biology↗

bioRxiv2024

SIGNAL-seq: Multimodal Single-cell Inter- and Intra-cellular Signalling Analysis

We present SIGNAL-seq (Split-pool Indexing siG-Nalling AnaLysis by sequencing): a multiplexed splitpool combinatorial barcoding method that simultaneously measures RNA and post-translational modifications (PTMs) in fixed single cells from 3D models. SIGNAL-seq PTM measurements are equivalent to mass cytometry and RNA gene detection is analogous to split-pool barcoding scRNA-seq. By measuring both mRNA ligand-receptor pairs and PTMs in single cells, SIGNAL-seq can simultaneously uncover inter- and intra-cellular regulation of tumour microenvironment plasticity.

cancer biology↗