Epithelial Stem Cell Fate Determines Chemoradiotherapy Response in Rectal Cancer

Li, N.; Ishaqwala, F.; Wright, T. A.; Wilkinson, A.; Vlckova, P.; Trevers, K.; O'Sullivan, R.; Crampsie, S.; Basiarz, E.; Vanderkamp, S.; McCulloch, A. K.; Dobric, A.; Krishnaswamy, S.; Vanhaesebroeck, B.; Glasgow Serial Sampling Consortium,; Roxburgh, C. S. D.; Hawkins, M.; Tape, C. J.

doi:10.64898/2026.07.15.736775

bioRxiv · 10.64898/2026.07.15.736775

Epithelial Stem Cell Fate Determines Chemoradiotherapy Response in Rectal Cancer

Li, N.·Ishaqwala, F.·Wright, T. A.·Wilkinson, A.·Vlckova, P.·Trevers, K.·O'Sullivan, R.·Crampsie, S.·Basiarz, E.·Vanderkamp, S.·McCulloch, A. K.·Dobric, A.·Krishnaswamy, S.·Vanhaesebroeck, B.·Glasgow Serial Sampling Consortium,·Roxburgh, C. S. D.·Hawkins, M.·Tape, C. J.

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Abstract

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

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Li, N., Ishaqwala, F., Wright, T. A., Wilkinson, A., Vlckova, P., Trevers, K., O'Sullivan, R., Crampsie, S., Basiarz, E., Vanderkamp, S., McCulloch, A. K., Dobric, A., Krishnaswamy, S., Vanhaesebroeck, B., Glasgow Serial Sampling Consortium,, Roxburgh, C. S. D., Hawkins, M., Tape, C. J.. 2026-07-15. Epithelial Stem Cell Fate Determines Chemoradiotherapy Response in Rectal Cancer. https://doi.org/10.64898/2026.07.15.736775

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