Stem Cell Transitions in Oncogenesis Highlight Lineage Vulnerabilities

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.

本研究采用相关技术，构建了源自人体的、与患者匹配的食管腺癌（oesophageal adenocarcinoma, EAC）及其癌前病变——巴雷特食管（Barrett's oesophagus）、低级别上皮内瘤变（low-grade dysplasia, LGD）、高级别上皮内瘤变（high-grade dysplasia, HGD）——的功能定义干细胞文库。这些克隆所支撑的高分辨率系统发育分析（high-resolution phylogenetic analysis），明确了肿瘤演进过程中突变阈值逐步递减的规律。尤为重要的是，可选择性清除多名患者来源巴雷特食管干细胞的药物组合（drug combinations），对LGD、HGD及EAC的干细胞均展现出相似的杀伤效能，这提示我们可通过靶向惰性癌前病变，识别增殖侵袭性更强的病变中共有的谱系脆弱靶点，为相关抗肿瘤治疗提供潜在可行策略。