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Cancer Research UK Cambridge Institute

 

Membrane Potential and Stem Cell Potency in Normal and Malignant Tissues

Background

The processes that regulate multipotency – the ability of a cell to differentiate into multiple different cell types – remain largely unknown.  Multipotency is a critical property of normal stem and progenitor cells and subpopulations of malignant cells that generate more differentiated daughter cells.  Better understanding of the processes that govern differentiation and lineage commitment hold promise to advance the fields of regenerative medicine and oncology. To identify novel genes that regulate multipotency, we generated a multi-organ murine cancer and lineage tracing model by recombining conditional oncogene, tumour suppressor gene (TSG) and lineage tracing alleles in cells expressing Cre-recombinase from the Promin1 locus: Promin1 marks stem and progenitor cells in several organ types1 (Figure 4). By comparing the whole cell transcriptomes of normal gastric stem cells and their daughter malignant stem cells that generate gastric adenocarcinomas, we identified a small number of genes, several ion channels and solute carriers that were selectively silenced in the malignant stem population.

Current research

We are generating a series of knock-in and knock-out models of ion channels to study their role in normal and malignant differentiation in tissues, with particular interest in the intestine.

Figure 4: Prom1+ cells (green) are source of stem cells for normal and maligant growth in the small intestine. Cartoon depicting how a conditional reporter allele (GFP) was recombined in the Prom1+ cells (bottom of crypt) in small intestine. Cells subsequently produce daughter cells that contribute to normal small intestine development (left) or become source of maligant growth (right), when oncogenes or tumour suppressor genes are recombined in Prom1+ cells.

References

1. Zhu, L., et al., Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation. Nature, 457: 603-7, 2009.