Understanding the regulatory chromatin landscape of oesophageal cancer

About the Project

Oesophageal adenocarcinoma (OAC) is a deadly disease with poor survival statistics, is one of the highest incidence cancer types and is growing in prevalence, particularly in the developing world. A major reason for this, is the lack of treatment options, due mainly to our lack of knowledge of molecular targets that arise from a detailed molecular understanding of the disease. Ove the past decade, our own work has helped to bridge this gap by investigating the gene regulatory mechanisms that lead to and maintain the cancer state in OAC (eg see Rogerson et al., 2019; Ogden et al., 2022; Ahmed et al., 2023; Yang et al., 2024). However, numerous questions remain. For example, although we have discovered that the precursor metaplastic state, Barrett’s oesophagus, shares gene regulatory networks with early developmental populations (Baker et al., 2023), how this is reconfigured in OAC progression and then reutilised following therapeutic drug treatment is poorly understood. Furthermore, there are numerous uncharacterised gene regulatory proteins beyond these networks that have been implicated in OAC, and we have identified dozens of potential new players from a recent CRISPR viability screen.

Projects are available to dissect and understand the gene regulatory networks that are operational during OAC progression, how these relate to developmental events and how they are repurposed to survive therapeutic insults. We are interested in both transcription factors and chromatin associated proteins and how they work in these contexts. A combination of detailed molecular and genome-wide approaches will be used, supplemented by computational methodologies. Recognising the complexity and heterogeneity of OAC, we will also incorporate single cell technologies to understand the gene regulatory networks that are operational in different subpopulations typically found in a patient. These studies will generate more effective therapeutic opportunities to combat this deadly disease.

Eligibility

Candidates are expected to hold (or be about to obtain) a minimum of a high scoring upper second class honours degree (or equivalent) in a related area / subject.  Candidates with experience in genome-wide approaches (experimental and computational) and with an interest in understanding how gene regulatory networks are reprogrammed in disease states such as cancer are encouraged to apply.

Before you Apply

Applicants mustmake direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.

How to Apply

To be considered for this project you MUST submit a formal online application form – on the application form select PhD Molecular Biology Programme. Full details on how to apply can be found on the Website: How to apply for postgraduate research at The University of Manchester

If you have any queries regarding making an application please contact our admissions team FBMH.doctoralacademy.admissions@manchester.ac.uk

Equality, Diversity and Inclusion

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website: Equality, diversity and inclusion (EDI | Postgraduate Research | Biology, Medicine and Health | University of Manchester

Funding Notes

Applications are invited from self-funded students. This project has a Band 3 (high) fee. Details of our different fee bands can be found on our website View Website

References

Rogerson C., Britton, E., Withey, S., Hanley, N., Ang, Y. and Sharrocks, A.D. (2019) Identification of a primitive intestinal transcription factor network shared between oesophageal adenocarcinoma and its pre-cancerous precursor state. Genome Research. 29(5):723-736.
Ogden, S., Carys, K., Ahmed, I., Bruce, J. and Sharrocks, A.D. (2022) Regulatory chromatin rewiring promotes metabolic switching during adaptation to oncogenic receptor tyrosine kinase inhibition. Oncogene. 41(43):4808-4822.
Ahmed, I., Yang, S-H., Ogden, S., Zhang, W., Li, Y., the OCCAMS consortium, Sharrocks, A.D. (2023) eRNA profiling uncovers the enhancer landscape of oesophageal adenocarcinoma and reveals new deregulated pathways. eLife. 12:e80840.
Yang, S-H., Ahmed, I., Li, Y., Bleaney, C.W., Sharrocks, A.D. (2024) Massively Parallel Reporter Assays identify enhancer elements in Oesophageal Adenocarcinoma. NAR Cancer. 6(4):zcae041.
Baker SM, Mullan A, Jennings RE, Piper-Hanley K, Ang Y, Palles C, Hanley NA, Sharrocks AD. The metaplastic precursor state to oesophageal adenocarcinoma represents reversion to a transient epithelial cell state in the developing oesophagus. 2024. BioRkiv. doi: https://doi.org/10.1101/2024.07.25.605105.