Dominique Bonnet

Investigation of the role of regulatory molecules in the self-renewal of human haematopoietic stem cell

Whereas it was previously believed that most or all cancer cells possess the property to self renew and replenish new cancer cells, it has recently become clear that cancers, as most normal tissues, are organized in a hierarchical fashion, and that only a small fraction of tumor cells have the ability to reconstitute a new tumor¹. The existence of such cancer stem cells (CSCs) with self-renewal potential was first documented in leukaemias², but has later been extended to solid tumours, including breast cancer³.

As these rare CSCs are both required and sufficient to reconstitute a new tumour, they have immediate and important clinical implications. Thus, it has become evident, that CSCs might prove not only to be the most important but also difficult cancer cells to eliminate with conventional therapies, and that a specific monitoring and targeting of the elusive CSCs could become an important tool towards identification and characterization of improved cellular and molecular targets for development of improved cancer therapies.

A number of regulatory molecules such as Wnt/β-catenin; Bmi-1, Gfi-1, Notch have been implicated in the maintenance of the self-renewal of mouse HSC. At present nothing is known about their roles in the regulation of normal HSC and LSC. This project will aim at addressing the role of known regulatory pathways on normal and LSC.

This project will involve:

• cloning of the specific regulatory molecules in inducible lentivirus vectors
• transduction of both normal and leukaemic stem cells
• functional studies using both in vitro and in vivo assays
• gene profiling using microarray analysis

References

1. Reya T, Morrison SJ, Clarke MF, Weissman IL. (2001). Stem cells, cancer, and cancer stem cells. Nature 2001; 414: 105.
2. Bonnet D, Dick JE. (1997). Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997; 3: 730.
3. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. (2003). Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 2003; 100: 3983.