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Investigating differentiation processes in normal and tumoral cells which affect phenotypic heterogeneity and stemness


Project Description

Our research is focused on understanding tissue renewal in health and disease using the intestine as a model system to study adult stem cell biology for a therapeutic benefit. (Ordóñez-Morán et al., Cancer Cell, Gjorevski et al., Nature). The intestinal epithelium is the most rapidly self-renewing tissue in mammals and its vigorous regeneration is enabled by highly active intestinal stem cells. We have recently described that differentiating cancer stem cells inhibits colorectal cancer progression (Ordóñez-Morán et al., Cancer Cell).

Cancer is one of the leading causes of death world-wide therefore there is an urgent need for more fruitful treatments for cancer patients. At advanced stages of disease, conventional therapies are ineffective due to a small population of drug-resistant cells called cancer stem cells that can reform the tumour. Indeed, the spread of these cells to distant organs accounts for over 90% of patient deaths. Our aim is to discover how these resistant cells can be efficiently and permanently eliminated.

Thus, our research is focused on the novel regulatory mechanisms which govern the balance between stem cell maintenance and differentiation. Furthermore, by disentangling the heterogeneity within the tumour, we aim to identify the key players and properties that enable stem cells to cause cancer growth and spreading. We will also study the mechanisms involved in cell plasticity to understand how cancer cells respond to conventional therapies depending on their state. To this end, we will use mouse models, clinical association analyses, high-throughput approaches, next-generation sequencing, single cell technologies, patient-derived material and 3D organoids which very well models intra-tumour heterogeneity.

Our main goals are

• Characterize the cells that are resistant to current therapies.
• Force cancer cells to change their properties (lose their stemness becoming differentiated cells) so that they can no longer divide and reform a tumour.
• Understand the reversibility of the stemness process (as differentiated cells can also gain stem cell properties). It will help us to design trials to overcome resistance.
• Study how these resistant cells can be targeted by novel approaches or drug combinations.

By tackling the above-mentioned research goals, we hope to improve treatment of cancer by:
• Identifying patients that are likely to relapse and/or stop responding to the treatment.
• Reduce the number of possible therapeutic strategies.
• Design novel drug combinations to increase rates of response and cure through more precise use of cancer therapies.
• Improve patient’s survival.

Start dates are October, December, February and April each year.

How to apply

To be considered for this studentship, please apply online at: https://www.nottingham.ac.uk/pgstudy/course/research/Medicine-PhD

Please include in your application:
• A detailed CV;
• Names and addresses of three referees;
• A covering letter highlighting your research experience/capabilities;
• At the top of your covering letter please put the name of your proposed supervisor and the title of the research

Funding Notes

We will consider applications from self-funded prospective students with:
• a good biomedical or related degree, with interests in any of the areas outlined above,
• a good command of the English language (written and spoken) as outlined in the postgraduate prospectus,
• competence with computers and data handling,
• a source of funding to cover tuition fees and bench fees (note that tuition fees are different for Home and EU students than for International students). More information regarding fees can be found under the ‘Medicine’ heading at: View Website

References

Gjorevski N, Sachs N, Manfrin A, Giger S, Bragina M, Ordóñez-Morán P*, Clevers H, Lutolf M. Designer matrices for intestinal stem cell and organoid culture. Nature 2016, Nov 24, 560-564 (* signed as independent researcher).
Ordóñez-Morán P, Dafflon C, Imajo M, Nishida E, Huelsken J. HOXA5 counteracts stem cell traits by inhibiting Wnt signaling in colorectal cancer. Cancer Cell 2015, Dec 14, 815-829.

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