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(WIS) Deciphering escape from senescence in vivo


Project Description

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 and conduce to inflammation and the progression of ageing-related disease including cancer. Cellular senescence has been identified to arise as a response to numerous stressogenic stimuli. In that case, of potentially damaging stress 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 to the irreversible encounter of the damage 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 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 fact that the 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 that encompass the parameter of cell-stroma interaction 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 eciting, 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. 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 transaltional cancer research.

Entry Requirements:
Applications should be submitted online and candidates should make direct contact with the Manchester supervisor to discuss their application directly. 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 project is to be funded under The University of Manchester and Weizmann Institute of Science Studentship. Funding covers fees (UK/EU rate) and stipend for four years. Candidates will be required to split their time between Manchester and Israel, as outlined on View Website

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.

References

1) Cell (2019) 179(4):813-827;
2) Nat. Cell Biol. (2016) 18(7):777-89;
3) BMC Genomics (2018) 19(1):37
4) Nature (2018) 553(7686):96-100;
5) Aging Cell (2017) 16:192–197;
6) Cold Spring Harb Perspect Biol 2010; 2: a001107;
7) Cancer Cell (2013) 23:634-46;
8) Oncogene (2018) 37:1669-84

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