Yue Sarah S K, Tong Yin, Siu Hoi Cheong, Ho Siu Lun, Law Simon Y K, Tsui Wai Yin, Chan Dessy, Huang Yuanhua, Chan Annie S Y, Yun Shui Wa, Hui Ho Sang, Choi Jee-Eun, Hsu Matthew S S, Lai Frank P L, Chan April S, Yuen Siu Tsan, Clevers Hans, Leung Suet Yi, Yan Helen H N
Department of Pathology, School of Clinical Medicine, Queen Mary Hospital, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China.
Gut. 2025 Mar 6;74(4):522-538. doi: 10.1136/gutjnl-2024-332594.
Gastric intestinal metaplasia (IM) is a precancerous stage spanning a morphological spectrum that is poorly represented by human cell line models.
We aim to establish and characterise human IM cell models to better understand IM progression along the cancer spectrum.
A large human gastric IM organoid (IMO) cohort (n=28), their clonal derivatives and normal gastric organoids (n=42) for comparison were established. Comprehensive multi-omics profiling and functional characterisation were performed.
Single-cell transcriptomes revealed IMO cells spanning a spectrum from hybrid gastric/intestinal to advanced intestinal differentiation. Their lineage trajectories connected different cycling and quiescent stem and progenitors, highlighting differences in gastric to IM transition and the potential origin of IM from cycling isthmus stem cells. Hybrid IMOs showed impaired differentiation potential, high lineage plasticity beyond gastric or intestinal fates and reactivation of a fetal gene programme.Cell populations in gastric IM and cancer tissues were highly similar to those derived from IMOs and exhibited a fetal signature. Genomically, IMOs showed elevated mutation burden, frequent chromosome 20 gain and epigenetic deregulation of many intestinal and gastric genes. Functionally, IMOs were FGF10 independent and showed downregulated FGFR2. Several IMOs exhibited a cell-matrix adhesion independent subpopulation that displayed chromosome 20 gain but lacked key cancer driver mutations, potentially representing the earliest neoplastic precursor of IM-induced gastric cancer.
Overall, our IMO biobank captured the heterogeneous nature of IM, revealing mechanistic insights on IM pathogenesis and progression, offering an ideal platform for studying early gastric neoplastic transformation and chemoprevention.
胃肠化生（IM）是一个癌前阶段，其形态学谱系范围较广，人类细胞系模型难以充分体现。
我们旨在建立并表征人类IM细胞模型，以更好地理解IM在癌症谱系中的进展。
建立了一个大型人类胃IM类器官（IMO）队列（n = 28）、其克隆衍生物以及用于比较的正常胃类器官（n = 42）。进行了全面的多组学分析和功能表征。
单细胞转录组显示IMO细胞跨越了从混合胃/肠到晚期肠分化的谱系。它们的谱系轨迹连接了不同的循环和静止干细胞及祖细胞，突出了胃向IM转变的差异以及IM可能起源于循环峡部干细胞。混合IMO显示出分化潜能受损、具有超越胃或肠命运的高谱系可塑性以及胎儿基因程序的重新激活。胃IM和癌组织中的细胞群体与源自IMO的细胞群体高度相似，并表现出胎儿特征。在基因组方面，IMO显示出突变负担增加、频繁的20号染色体增益以及许多肠和胃基因的表观遗传失调。在功能上，IMO不依赖FGF10且FGFR2表达下调。几个IMO表现出一个不依赖细胞-基质黏附的亚群，该亚群显示20号染色体增益但缺乏关键的癌症驱动突变，可能代表IM诱导的胃癌的最早肿瘤前体。
总体而言，我们的IMO生物样本库捕捉到了IM的异质性，揭示了IM发病机制和进展的机制性见解，为研究早期胃肿瘤转化和化学预防提供了理想平台。
