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  Decoding the epigenetic mechanisms of drug resistance in aggressive breast cancers


   Faculty of Biology, Medicine and Health

  , ,  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Breast cancers pose a major health burden to modern world as being the most common cancer in women. Estrogen receptor (ER), the classical marker of 70% these cancers, is the nuclear receptor important for cancer progression. Even though survival rates of these cancer patients have increased in recent years due to the development of ER targeting agents, drug resistance and metastasis to other organs are the major causes of cancer-related deaths. Several studies had identified various mutations enriched in these aggressive cancers comparing to the primary tumours which respond to treatments. Understanding how specific gene mutations make cancer cells to relapse after treatment is essential to improve patient outcome.

Our previous studies established high-throughput genome-wide CRISPR screens which identified novel role of chromatin associated proteins in promoting drug resistance in ER+ breast cancer cells in their absence [1,2]. One such class of proteins are chromatin architectural proteins which mediate long range chromosomal interactions to regulate gene expression. Our CRISPR screens identified these proteins in promoting response to ER targeting agents in breast cancer cell lines. Interestingly, these complexes are mostly inactivated by mutations in metastatic breast cancers which supports the significance of our study.

By utilising systematic and unbiased methods (next generation sequencing and quantitative proteomics) in clinically relevant in vivo systems, this PhD project is proposed to discover the role of frequently represented alterations in chromatin architectural proteins in mediating drug resistance and the potential impact of epigenetic inhibitors in overcoming resistance to the existing therapies in breast cancers. This study will provide mechanistic insights and the importance of epigenetic proteins in driving tumour relapse and potential therapeutic strategies to target these aggressive tumours.

Training/techniques

The project will utilise the CRISPR-Cas9 edited knockout on breast cancer cells to investigate the impact of chromatin associated proteins-specific alterations in drug resistance using cutting-edge technologies, including qPLEX RIME (Quantitative Rapid Immunoprecipitation and Mass-spectrometry of endogenous proteins [3]), ChIP-sequencing and ChIA-Drop (chromatin architecture studies [4]) to define the functional interplay of the chromatin-associated proteins and nuclear receptors. This will employ cell lines- and patient-derived xenografts to reflect the human disease. We will assess the efficacy of epigenetic inhibitors targeting alteration-specific enriched proteins to explore their effect in tumour growth using high throughput cell viability screens.

Eligibility 

Applicants must have obtained or be about to obtain a First or Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in a relevant subject area. Applicants with experience in molecular biology techniques, next generation sequencing and CRISPR platforms are encouraged to apply. Additional expertise in bioinformatics approaches is desirable. A keen interest in studying gene regulatory mechanisms and epigenetics is essential.

Before you Apply 

Applicants must make 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 

For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor. On the online application form select the appropriate subject title - PhD Cancer Sciences.

For international students, we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit https://www.bmh.manchester.ac.uk/study/research/international-phd/

Your application form must be accompanied by a number of supporting documents by the advertised deadlines. Without all the required documents submitted at the time of application, your application will not be processed and we cannot accept responsibility for late or missed deadlines. Incomplete applications will not be considered. If you have any queries regarding making an application please contact our admissions team   

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

Biological Sciences (4)

Funding Notes

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

References

1. Nagarajan S, Rao SV, Sutton J, Cheeseman D, Dunn S, Papachristou EK, Prada J-EG, Couturier D-L, Kumar S, Kishore K, Chilamakuri CSR, Glont S-E, Archer Goode E, Brodie C, Guppy N, Natrajan R, Bruna A, Caldas C, Russell A, Siersbæk R, Yusa K, Chernukhin I, Carroll JS. ARID1A influences HDAC1/BRD4 activity, intrinsic proliferative capacity and breast cancer treatment response. Nature Genetics. 2020;52(2):187–97.
2. Xu G, Chhangawala S, Cocco E, Razavi P, Cai Y, Otto JE, Ferrando L, Selenica P, Ladewig E, Chan C, Paula ADC, Witkin M, Cheng Y, Park J, Serna-Tamayo C, Zhao H, Wu F, Sallaku M, Qu X, Zhao A, Collings CK, D’Avino AR, Jhaveri K, Koche R, Levine RL, Reis-Filho JS, Kadoch C, Scaltriti M, Leslie CS, Baselga J, Toska E. ARID1A determines luminal identity and therapeutic response in estrogen-receptor-positive breast cancer. Nature Genetics. 2020;52(2):198–207.
3. Papachristou EK, Kishore K, Holding AN, Harvey K, Roumeliotis TI, Chilamakuri CSR, Omarjee S, Chia KM, Swarbrick A, Lim E, Markowetz F, Eldridge M, Siersbaek R, D’Santos CS, Carroll JS. A quantitative mass spectrometry-based approach to monitor the dynamics of endogenous chromatin-associated protein complexes. Nat Commun. 2018;9(1):2311.
4. Zheng M, Tian SZ, Capurso D, Kim M, Maurya R, Lee B, Piecuch E, Gong L, Zhu JJ, Li Z, Wong CH, Ngan CY, Wang P, Ruan X, Wei C-L, Ruan Y. Multiplex chromatin interactions with single-molecule precision. Nature. 2019;566(7745):558–62.

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