Stem Cell Transitions in Oncogenesis Highlight Lineage Vulnerabilities. Homo sapiens

We employed technologies to generate libraries of functionally defined stem cells of patient-matched oesophageal adenocarcinoma (EAC) and its precursor lesions (Barrett's oesophagus, low-grade dysplasia (LGD), high-grade dysplasia (HGD) ) from human. The high-resolution phylogenetic analysis enabled by these clones defines a successively diminishing mutational threshold for transitions. Importantly, drug combinations that selectively eliminate Barrett's stem cells derived from multiple patients show similar efficacy against stem cells of LGD, HGD, and EAC, suggesting the potential of exploiting indolent precursor lesions to identify common lineage vulnerabilities in more proliferatively aggressive lesions.