Fatehullah, A., Terakado, Y., Sagiraju, S., Tan, T. L., Sheng, T., Tan, S. H., … Barker, N. (2021). A tumour-resident Lgr5+ stem-cell-like pool drives the establishment and progression of advanced gastric cancers. Nature Cell Biology, 23(12), 1299–1313. doi:10.1038/s41556-021-00793-9
Abstract:
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.
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Funding Info:
This research / project is supported by the National Medical Research Council - YIRG
Grant Reference no. : MOH-000366
This research / project is supported by the National Research Foundation - IRG
Grant Reference no. : NRFI2017-03
i) Japan Society for the Promotion of Science (JSPS) KAKENHI (grant number 17H01399)
ii) JSPS KAKENHI grant number 17H06710
iii) JSPS KAKENHI grant number 17K07161