Multiomic investigation of the molecular mechanisms during differential treatment response in breast cancers

Closing date: 25/03/2024

MB-PhD Project: Multiomic investigation of the molecular mechanisms during differential treatment response in breast cancers

Lead Supervisors: Dr Sankari Nagarajan 
Co-Supervisors:
Dr Sumitra Mohan, Prof. Robert Clarke, Prof. David Wedge, Prof. Cliona Kirwan, Dr Ciara O’ Brien

Applications Deadline: Monday 25 March 2024

Project Keywords: Cancer reprogramming; Lobular breast cancers; Proteomics; Genomics; Epigenomics
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.

Project Outline

Lobular breast cancers represent one of the understudied cancers but of unmet need, due to their poor response to targeted therapies. Failure in drug response is often associated with differential molecular changes in cancer cells according to the origin of the tumour (ductal or lobular), either associated with DNA sequences (genetic) or other than DNA that affect gene expression (so-called epigenetic alterations). Understanding the coupled genetic and epigenetic reprogramming is critical to reveal the key regulators of treatment response. However, this interactive reprogramming is poorly understood in any cancers, let alone lobular cancers. Moreover, our current knowledge on these cancers includes evidence accumulated from in vitro-based studies which doesn’t properly replicate the patient samples.  

This project aims to understand the previously unknown lobular-specific genetic and epigenetic reprogramming via studying gene alterations, proteomic interaction landscape and changes in the activity and expression of coding and non-coding RNAs (enhancer RNAs, eRNAs) from gene regulatory DNA elements called enhancers on primary tumour tissues. Our study will explore the following: 

  • Identify the gene alteration profiles of the tumour samples 
  • investigate the mutation-specific protein interactome and expression of eRNAs 
  • validate and assess the function of differential protein network and eRNAs 

Importantly, our comparative analysis with lobular and ductal samples for specific gene mutations will allow us to identify mechanisms of differential treatment response to already existing therapies, which can indicate potential effective therapeutic approaches.  

The proposed study will utilise a multidisciplinary supervisory team with lot of training opportunities for students in targeted genetic profiling, interaction proteomic analyses and high throughput transcriptional profiling. We successfully obtained access to lobular and ductal tumour samples with matched FFPE and frozen material from Breast Cancer Now Tissue biobank for this study. This will be an unbiased one-of-a-kind study investigating the interactive genetic and epigenetic reprogramming in controlling treatment response. 

About Prof. Sankari Nagarajan (project Lead Supervisor)

Nagarajan’s lab is interested in unravelling the mechanisms of enhancer regulation and the role of transcription factors in mediating the progression to drug resistance and metastasis in aggressive cancers. Dr Sankari Nagarajan’s lab utilise single cell analyses, functional genomic technologies, quantitative chromatin-based proteomics and CRISPR-Cas9 assays to decipher the mechanisms of transcription. The lab work on the following projects:

1. Understanding the role of chromatin-associated proteins in driving endocrine resistance in breast and prostate cancers

2. Deciphering the activity of enhancers and transcription factors regulated by chromatin remodelling complexes

3. Single cell epigenomics to investigate the molecular mechanisms of metastasis in aggressive cancers

4. Enhancer-derived RNAs as markers for enhancer regulation in aggressive breast cancers

Find out more

Headshot of Prof. Sankari Nagarajan

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