GSE184613
A Tumour-Resident Lgr5+ Stem Cell - Like Pool Drives the Establishment and Progression of Advanced Gastric Cancers
Gastric cancer is amongst the most prevalent and deadliest cancers globally. To derive mechanistic insight into the pathways governing this disease, we generated a stomach-specific Claudin18-IRES-CreERT2 mouse line to model advanced human gastric cancer and investigated the role of tumour resident Lgr5+ stem-like cells in gastric cancer. Mouse lines incorporating Cldn18-driven conditional dysregulation of the Wnt, RTK and Trp53 pathways modelled metastatic Chromosomal Instable-type gastric cancer. In parallel, we supplemented these cancer models with orthotopic transplantation of cancer organoids to derive detailed mechanistic insight into the roles of Lgr5+ cancer stem cell in gastric cancer. Here we show, we recapitulated advanced human gastric cancer in terms of disease phenotype, aberrant gene expression profile, molecular markers, and sites of distant metastases. Importantly, we established that tumour-resident Lgr5+ stem-like cells are critical to the initiation and maintenance of tumour burden, and are obligatory for the establishment of metastases. These models will be invaluable for deriving clinically-relevant mechanistic insights into cancer progression and as pre-clinical models for evaluating novel therapeutics. Overall design: Adult Cldn18-Apc(WT/Fl),Trp53(Fl/Fl),Kras(G12D) mice were induced with 100mg/kg tamoxifen. Tissue was harvested and tumours categorised as neoplastic or advanced/invasive. Tissue was lysed in Trizol and RNA extracted using Qiagen RNAEasy Kit. The libraries were constructed using NEBNext® Ultra™ Directional RNA Library Prep Kit for Illumina® and sequenced on an Illumina NovaSeq 6000 platform at Novogene, Singapore.