Prof P Townsend, Dr Jamie Honeychurch, Prof Vasileios Gorgoulis
No more applications being accepted
Competition Funded PhD Project (European/UK Students Only)
About the Project
Senescence is a dynamic cellular state characterised by a prolonged and generally irreversible cell-cycle arrest that promotes tissue remodelling but it can also have detrimental implications on regenerative capacities of tissues leading to inflammation and the progression of ageing-related disease including cancer. Cellular senescence arises as a response to numerous stressogenic stimuli. For example, potentially damaging ‘stressed cells’ have to undergo a decisive response that varies from the total reversion of the damage and the restoration of their structural and functional integrity. It is thought this damage is irreversible by activating death mechanisms principally to restrain the propagation of tissue degeneration. Between these extremes, cells can obtain other cellular states, often associated with survival as well as with permanent structural and functional changes. Senescence has been considered to represent a barrier against tumourigenesis, the rupture of which can lead to cancer initiation and further progression. According to a carcinogenesis model we have proposed, activated oncogenes, such as CDC6 and its interaction with p53, disrupt normal DNA replication provoking replication stress that in turn triggers the DNA damage response (DDR) pathway, promoting genomic instability and cancer development.
In line with our model and despite the belief that senescent arrest was considered to be irreversible, senescent cells have the potential to escape from senescence and resume with cell cycle progression. Notably, our in vitro data employing 2D cultures and 3D settings (recapitulating cell-stroma interactions) revealed that the escaped from senescence cells exhibited aggressive features, chemo-resistance and stemness. Given that several therapeutic modalities can trigger senescence in patient tumours, it is important to decipher in vivo escaped from senescence cells. These cells that recover and re-enter cell cycle may contribute to cancer recurrence. Hence, understanding the underlying biological phenomenon is of particular importance for cancer prognosis and therapy. Within this context, the development of pancreas-specific lineages studying the impact of CDC6 overexpression may provide a model to study pancreatic carcinogenesis within the context of the master tumour suppressor p53.
This is an exciting, state of the art, PhD studentship that will allow the student work on molecular and cellular biology approaches to understanding normal and oncogenic biology, ranging from cell, in vitro through to in vivo models of exploration. By working with our industrial partners, Waters, we will be able to interrogate the underlying ‘omic biology that will explain this senescence escape. We have a proven record of success and the student will be embedded in a fruitful, nurturing and world leading environment with the opportunity to work at the forefront of translational cancer research.
https://www.research.manchester.ac.uk/portal/paul.townsend.html
https://www.research.manchester.ac.uk/portal/jamie.honeychurch.html
https://www.gorgoulis.gr/
https://www.waters.com/nextgen/gb/en.html
Entry Requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.
Funding Notes
This is a CASE studentship in partnership with Waters Corporation and will be funded under the MRC Doctoral Training Programme. If you are interested in this project, please make direct contact with the Supervisor to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found here https://www.bmh.manchester.ac.uk/study/research/mrc-dtp/apply/
As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.