Background:
Prostate cancers are the commonest malignancies in men. Androgen Receptor (AR) is the classical marker of most of these cancers, driving the cancer progression. Even though survival rates of the patients suffering from this cancer have increased in recent years due to the development of AR-targeting agents, drug resistance and metastasis to other organs are the major causes of cancer-related deaths. Understanding how specific gene mutations cause cancer cells to relapse after treatment is essential to improving patient outcomes.
Preliminary analyses from genome-wide CRISPR screens identified a novel role of chromatin architectural proteins, which mediate long-range chromosomal interactions, Mediator and Cohesin, in promoting response to an endocrine agent in a prostate cancer cell line. Interestingly, these complexes are mostly altered by mutations or amplifications in metastatic prostate cancers. This suggests an important and differential association of these proteins in prostate cancers in endocrine treatment response.
Aims:
In this project, the student will aim to understand how Mediator and Cohesin complex proteins regulate treatment resistance in prostate cancer patients differentially. They will investigate the transcriptional association of nuclear receptors with Mediator and Cohesin complexes and the gene regulatory networks regulated by these interactions. We will also identify the druggable chromatin-associated proteins, which are enriched in the context of Mediator and Cohesin alterations to overcome treatment resistance.
Methods:
We will utilise the CRISPR-Cas9 edited prostate cancer cell lines to investigate the impact of Mediator and Cohesin complex alterations in drug resistance using cutting-edge technologies, including qPLEX RIME (Quantitative Rapid Immunoprecipitation and Mass-spectrometry of endogenous proteins), Chromatin Immunoprecipitation (ChIP-sequencing) and HiChIP (ChIP-based chromatin architecture studies) to define the functional interplay of the Mediator, Cohesin and AR. We will employ cell lines and patient-derived xenografts reflecting the human disease. We will assess the efficacy of epigenetic inhibitors targeting the enriched proteins to explore their effect on tumour growth.
Impact:
By utilising CRISPR models and clinically relevant in vivo systems, we can systematically discover the role of frequently represented alterations in chromatin architecture proteins and the potential impact of epigenetic inhibitors in overcoming resistance to the existing therapies in prostate cancers. This study will provide mechanistic insights into tumour relapse and potential therapeutic strategies to target these aggressive tumours.
Entry Requirements
Applicants should hold (or be about to obtain) a First or Upper Second class (2:1) UK honours degree, or international equivalent, in a relevant subject.
Application Guidance
Candidates must contact the primary supervisor before applying to discuss their interest in the project and assess their suitability.
Apply directly via this link:
MRC DTP PhD Programme
or on the online application portal, select MRC DTP PhD Programme as the programme of study.
You may apply for up to two projects within this scheme. To do so, submit a single online application listing both project titles and the names of both main supervisors in the relevant sections.
Please ensure that your application includes all required supporting documents:
· Curriculum Vitae (CV)
· Supporting Statement
· Academic Certificates and Transcripts
Incomplete or late applications will not be considered. Further details are available on our website:
MRC Doctoral Training Partnership | Biology, Medicine and Health | University of Manchester
Equality, diversity and inclusion are central to the University’s activities. The full statement can be found here: https://www.bmh.manchester.ac.uk/study/research/getting-started/equality-diversity-inclusion/