Closing date: 03/02/2023
MB-PhD Project: Single cell resolution mapping of metastasis using quasi vivo models in estrogen receptor-positive breast cancers
Initial Intercalation Deadline: 12 December 2022
Interviews: Tuesday 7 March 2023
Final Deadline for Permission to Intercalate (UoM Programmes): 26 May 2023
MB-PhD start date: September 2023
Project Keywords: Metastasis, breast cancer, epigenetics
Research Opportunity: Intercalated PhD, leading to the award of PhD and MBChB
Applications for this project are now open. Candidates must contact prospective supervisor/s ahead of submitting an application. See the MB-PhD programme page for details of how to apply.
Breast cancer is the most common cancer in women and almost 70% of these cancers are driven by hormones. Despite the frequency of incidence, most women survive with breast cancer due to the development of targeted therapies against the major hormone receptor, estrogen receptor (ER). However, around 20-30% of patients don’t respond to these therapies and present with significant relapse and metastatic spread to other organs which leads to death.
Recent studies highlighted enrichment of inactivating mutations in the subunits of chromatin remodelling complexes, especially a subunit ARID1A in relapsed/metastatic breast cancers and the importance of these complexes in controlling response to ER-targeting agents. Understanding how metastasis is controlled by chromatin remodellers would provide alternative therapeutic strategies favourable to the patients with specific alterations. However, there are no appropriate robust models to study metastasis in shorter time frame with the elements of tumour microenvironment and target homing tissues, where we can manipulate the functions of genes.
In this study, the student will utilise the Quasi vivo culture system, where we can grow MCF7 breast tumour cell line genetically altered to perturb expression of ARID1A, lung-specific cells and fibroblasts in separate but interconnected chambers, resembling the human system. This system will robustly be used to explore the molecular changes happening during the priming, migration and colonisation of cancer cells to the lung system in a real and shorter time frame comparing to mice tissue, as the cells can be visualised easily, as grown on cover slips.
The student will investigate the transcriptional and chromatin-level changes at single cell resolution to understand the dynamic reprogramming of transcription and driving transcription factors between tumour and lung cells, providing an interactive epigenetic landscape. Overall, our study will establish a comprehensive and integrative analyses of how metastasis is established due to specific genetic alterations which are enriched in metastatic patients, emphasising personalised and targeted therapeutics.
About the Nagarajan Lab
Me as a PhD lead supervisor
I would like to explore how cancer cells can move to a completely different organ, make other type of normal cells to interact with them, if successful, can grow there to form metastasis. This interaction is quite successful for cancer cells, but what does the other organ type cells go through?
Lab environment and culture
The research lab you will end up with is very important in shaping your career and goals of your life. Nagarajan lab is just established with young people who are quite vibrant and enthusiastic who treat each other friendly. Our lab is communicative and very supportive. It is one of the lab where people meet often outside for coffee, drinks and dinner.
Research expectations and meetings
I expect the student to be more interactive in the meetings. There is no question called as stupid question up to me. I also expect the student to take control over the project and develop it with their own ideas. It should be a collaboration between the student and the supervisor rather than a dictatorship.
How you encourage independence and career development I really love the independence I experience since my Postdoc. I would like to guide the student to explore the same. I will support their career path as much as possible and they will be provided with all the independence to choose what it should be.
I run mentorship schemes for my Division. In addition to being a mentor myself to the student, I will make sure the student gets another mentor that they can get guidance on anything they need help with.
I recommend no work out of hours and during weekends. I myself have a one year old baby and I highly recommend everyone in my lab to have their own life and spend more time with family. Work smart butnot too hard.
Find out more about the MB-PhD Programme in Manchester and our current MB-PhD students.