Gene regulatory networks driving metastatic progression in oesophageal adenocarcinoma

Closing date: 25/03/2024

MB-PhD Project: Gene regulatory networks driving metastatic progression in oesophageal adenocarcinoma

Lead Supervisors: Prof. Andrew Sharrocks
Prof. Yeng Ang

Applications Deadline: Monday 25 March 2024

Project Keywords: Oesophageal adenocarcinoma; Epigenetic regulation; Metastasis 
Research Opportunity: Intercalated PhD, leading to the award of PhD and MBChB

The project supervisor is offering a PhD in the below area during 2024/2025. Work during the Summer Placement might involve some of this work but could vary.

PhD Project Outline

Oesophageal adenocarcinoma (OAC) incidence is increasing and yet survival rates remain very poor. There are limited treatment options, especially for metastatic disease, which is especially problematic as patients usually present with late stage disease. Thus understanding the molecular basis to metastatic disease is a clear unmet need. 

There is a growing realisation that mutational changes in the genome are unlikely to explain how cells transition to the metastatic state and instead, epigenetic and associated gene regulatory changes likely play a major role in this transition. This project therefore aims to test this hypothesis and will identify and characterise the gene regulatory networks that define and sculpt the metastatic state in OAC cells through impacting on the regulatory chromatin landscape. 

This project will start with patient material and will use matched patient tumour samples to study disease progression. We have an ongoing rapid autopsy study established for sample collection. A range of ‘omic approaches will be implemented to define the regulatory pathways relevant to tumour metastasis. Regulatory networks will be derived through bioinformatic interrogation and subsequent work will validate a key regulator in cell line models by loss and gain of function approaches coupled to molecular, cellular and ‘omic methodologies. Importantly we will revalidate the mechanisms we uncover by integrating further patient derived data. 

By focussing on the underlying chromatin landscape, we will uncover the regulatory events that lead to acquisition and maintenance of the OAC metastatic state. This project will have direct clinical implications as we will identify potential targets and pathways for therapeutic intervention in OAC patients with metastatic disease. We will also establish molecular signatures and biomarkers for targeting treatment in a personalised manner.

About Prof. Andrew Sharrocks (project Lead Supervisor)

Professor Andy Sharrocks was appointed to the role of Associate Dean for Research Technology in October 2019, responsible for research technology development and infrastructure in the Faculty.

He is based in the Division of Molecular and Cellular Function, where his research interests include signal-mediated gene regulation and eukaryotic transcriptional control in relation to oesophageal cancer and stem cell differentiation.

Professor Sharrocks achieved an undergraduate degree in Biochemistry from Sheffield University and continued his studies there to complete a PhD studying prokaryotic transcriptional control mechanisms.

He subsequently continued his work on prokaryotic transcription factors in his first postdoctoral position, and moved to the Max Planck Institute in Freiburg, Germany to study eukaryotic transcriptional control mechanisms.

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Headshot of Prof. Andrew Sharrocks

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