A tumour-resident Lgr5+ stem-cell-like pool drives the establishment and progression of advanced gastric cancers.
A FatehullahY TerakadoS SagirajuT L TanT ShengS H TanK MurakamiY SwathiN AngRavisankar RajarethinamT MingPatrick Boon-Ooi TanB LeeNick BarkerPublished in: Nature cell biology (2021)
Gastric cancer is among the most prevalent and deadliest of cancers globally. To derive mechanistic insight into the pathways governing this disease, we generated a Claudin18-IRES-CreERT2 allele to selectively drive conditional dysregulation of the Wnt, Receptor Tyrosine Kinase and Trp53 pathways within the gastric epithelium. This resulted in highly reproducible metastatic, chromosomal-instable-type gastric cancer. In parallel, we developed orthotopic cancer organoid transplantation models to evaluate tumour-resident Lgr5+ populations as functional cancer stem cells via in vivo ablation. We show that Cldn18 tumours accurately recapitulate advanced human gastric cancer in terms of disease morphology, aberrant gene expression, molecular markers and sites of distant metastases. Importantly, we establish 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 preclinical models for evaluating therapeutic targets.
Keyphrases
- tyrosine kinase
- stem cells
- gene expression
- papillary thyroid
- patient safety
- cancer stem cells
- quality improvement
- squamous cell
- epidermal growth factor receptor
- childhood cancer
- dna methylation
- endothelial cells
- squamous cell carcinoma
- small cell lung cancer
- cell therapy
- lymph node
- emergency medicine
- cell proliferation
- copy number
- induced pluripotent stem cells
- single molecule
- mesenchymal stem cells
- radiofrequency ablation
- pluripotent stem cells
- genome wide