Understanding the heterogeneity and evolutionary dynamics of Barrett’s oesophagus to predict cancer risk

Many cancers evolve over years, offering a window to uncover the cellular and molecular changes that precede diagnosis, yet many are still detected at advanced stages. The precancerous lesion Barrett’s oesophagus (BO) provides a compelling model for studying these early events. While the driver gene landscape has been elucidated for this disease, little is known about why only a minority of BO patients progress while most remain indolent. We hypothesise that a biology-informed approach capturing dynamic molecular and cellular changes over time could transform current understanding and practice. We will leverage a comprehensive, longitudinal bioresource of BO progressors and non-progressors collected over 30 years, integrate cutting-edge single-cell and spatially resolved omics, and employ newly established multi-disease-stage organoid models to dissect the key events driving progression (or indolence). Our interdisciplinary team will investigate: (i) which cells are roots of progression at each disease stage; (ii) the timing, ordering and consequences of mutations; and (iii) how highly mutated BO reshapes its microenvironmental niche and evades immune surveillance. These data will feed into (iv) an integrative, dynamic statistical model incorporating time-dependent clinical, pathological and molecular variables to predict individual cancer risk.