(MCRC Non-Clinical) Oncogenic signalling through transcriptional repression pathways in oesophageal adenocarcino

Oesophageal adenocarcinoma (OAC) shows poor survival statistics and there is an urgent need to further understand which cellular pathways are subverted in this cancer and how they lead to phenotypic changes that characterise cancer cells. New molecular insights will provide new diagnostic opportunities and potential therapeutic targets. Sequencing of hundreds of OAC cancer genomes has revealed that the Receptor Tyrosine Kinase (RTK) pathways are often altered in OAC (>60% of cases) but the molecular consequences of RTK pathway hyperactivation are unclear. One such RTK, ERBB2, is a therapeutic target for patients with gastro-oesophageal adenocarcinoma but the clinical benefit is limited potentially due to resistance. During our studies of resistance mechanisms, we conducted a phospho-proteomics screen to identify ERBB2 targets and identified two transcriptional repressors, CIC and ERF which are potentially inactivated in OAC. We have proposed a “double lock” transcriptional repression mechanism whereby CIC represses the transcription of the transcriptional activator ETV4 (a known oncogenic transcription factor in OAC). A second repressor, ERF, is proposed to then directly compete with ETV4 for binding to chromatin, providing a failsafe mechanism. In the cancer scenario, this lock would be lost due to ERBB2-mediated repressor inactivation. In this project, we will test this model and determine how these two ERBB2-controlled transcriptional repressors function to suppress tumourigenic properties and how this is lifted following oncogenic RTK signalling in tumour cells. Further studies will examine repressor-mediated liquid-liquid phase separation (LLPS) as a novel concept through which gene expression is mediated in cancer cells. We will use a range of cellular, molecular, genome-wide and bioinformatics approaches to reveal the underlying mechanisms and determine their relevance in the context of patient-derived material.

Entry Requirements:
Candidates must hold, or be about to obtain, a minimum upper second class (or equivalent) undergraduate degree in a relevant subject. A related master’s degree would be an advantage.

UK applicants interested in this project should make direct contact with the Primary Supervisor to arrange to discuss the project further as soon as possible. International applicants (including EU nationals) must ensure they meet the academic eligibility criteria (including English Language) as outlined before contacting potential supervisors to express an interest in their project. Eligibility can be checked via the University Country Specific information page (https://www.manchester.ac.uk/study/international/country-specific-information/).

If your country is not listed you must contact the Doctoral Academy Admissions Team providing a detailed CV (to include academic qualifications – stating degree classification(s) and dates awarded) and relevant transcripts.

Following the review of your qualifications and with support from potential supervisor(s), you will be informed whether you can submit a formal online application.

To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the CRUK Manchester Centre PhD Training Scheme (MCRC) website https://www.bmh.manchester.ac.uk/study/research/funded-programmes/mcrc-training-scheme/

General enquiries can be directed to [Email Address Removed].

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 https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/

Interview date – 8 January 2021