Adult stem cells are rare tissue populations responsible for the remarkable self-renewal capacity of epithelia in organs such as the intestine, skin and stomach. We have recently identified a cell-surface marker (Lgr5) of these epithelial stem cells in the intestine, stomach, skin, kidney and ovary that has allowed us to intensively study their normal function during tissue renewal and also to evaluate their contribution to cancer. This has revealed important insights into how these stem cells effect daily tissue renewal and has proven that Lgr5-expressing stem cells are a major contributor to cancer formation and progression in various organs.
We employ a variety of genetic mouse models, including in-vivo lineage tracing, and ex-vivo organoid culture methods to dissect the role of Lgr5-expressing stem cells in epithelial self-renewal and cancer of various organs, including the stomach, ovary and mammary gland. The ultimate goal is to harness the regenerative capacity of these adult stem cells for therapeutic use, as well as developing ways of blocking the cancer-promoting activities of mutated Lgr5 stem cells.
To achieve this, we employ the following approaches:
- In-vivo lineage tracing using the Lgr5-EGFP-ires-CreERT2 mouse model in combination with state-of-the-art multi-color reporter mice to assess Lgr5 stem cell function during epithelial renewal.
- Intra-tumor lineage tracing from candidate Lgr5 cancer stem cell populations in mouse gastric cancer and ovarian cancer models.
- Targeted mutation of Lgr5 stem cells in the stomach and ovary using the Lgr5-EGFP-ires-CreERT2 mice in combination with conditional mouse lines to assess the tumor-initiating potential of the Lgr5 stem cells.
- Gene expression profiling of Lgr5 stem cell populations to reveal novel stem cell markers.
- Conditional knockdown of Lgr5 on adult stem cells and their cancer counterparts to assess Lgr5 function in-vivo.
- Develop human organoid culture systems for both basic research and potential therapeutic applications.
Agency for Science, Technology and Research (A*STAR), Singapore
- Professor Owen Sansom (Beatson Institute, Glasgow UK)
- Professor Alan Clarke (Cardiff, UK)
- Dr Elizabeth Vincan (Melbourne, Australia)