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Controlling stem cell differentiation and cancer progression by manipulating the crosstalk between Notch and Wnt signalling

  • Full or part time
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

The bewildering array of different cell types formed during the development of animals is controlled primarily by cell-cell signalling. However there are surprisingly few signalling pathways, with some suggesting that only seven or eight different pathways are used to generate the more than two hundred different cell types that make up a human. This raises the question of how the diversity of cell types is produced. In part, it can be explained by sequential use of different signalling pathways with cell fate being defined by the order and combination of pathways used. An alternative possibility is concurrent signalling between two or more pathways leading to the expression of fate-inducing genes that require co-operative binding between transcription factors that are activated by the different pathways. A final possibility is crosstalk between signalling pathways allowing one pathway to alter the output of another. Combining the output of different signalling pathways in this way to generate different cell types is rather like mixing and matching a small number of letters to generate hundreds of different words.

We are particularly interested in the crosstalk between the Notch and Wnt pathways. These are two of the most important signalling pathways in animal development and adult tissue maintenance. Also, their misregulation is associated with several human diseases, including congenital disorders and cancer. We have elucidated the molecular mechanisms underpinning several crosstalk mechanisms between these pathways in vertebrates. We are now interested in how these mechanisms are used during the self-renewal and differentiation of stem cells within the normal mammary gland, and are abused during breast cancer formation.

Funding Notes

This project has a Band 2 fee. Details of our different fee bands can be found on our website. For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website. Informal enquiries may be made directly to the primary supervisor.

References

• Pires-daSilva A, Sommer RJ: The evolution of signalling pathways in animal development. Nat Rev Genet 2003, 4(1):39-49.
• Bolos V, Grego-Bessa J, de la Pompa JL: Notch signaling in development and cancer. Endocr Rev 2007, 28(3):339-363.
• Luo J, Chen J, Deng ZL, Luo X, Song WX, Sharff KA, Tang N, Haydon RC, Luu HH, He TC: Wnt signaling and human diseases: what are the therapeutic implications? Lab Invest 2007, 87(2):97-103.
• Collu GM and Brennan K: Co-operation between Wnt and Notch signalling in human breast cancer. Breast Cancer Res 2007 9, 105-7.
• Collu GM, Hidalgo-Sastre A, Gildea C, Owens TW, Oliveira S, Bayston L, Dorey K and Brennan K: Dishevelled limits Notch signalling in vertebrates through inhibition of CSL transcription factors. Development 139, 4405-15.

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