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supervisors:

Dr Simon Lord and Prof  Skirmantas Kriaucionis

About the research: 

Adipocytes are one of the primary stromal cells in many tissues and adipocyte-cancer cell crosstalk has been shown to enhance tumour progression in preclinical models. There is potential to target these interactions for therapeutic benefit with greater characterisation of these complex relationships. We hypothesise that breast adipocytes within the tumour microenvironment display an altered phenotype that enables extraction of nutrients by tumour cells. To investigate this supposition we plan to characterise adipocytes from the tumour microenvironment and use matched ‘normal’ control adipocytes extracted from the non-involved breast (both taken during breast surgery). The Kriaucionis laboratory has already established single cell sequencing techniques and primary cell culture techniques using human breast cancer and breast adipose samples, alongside mass spectrometry techniques to trace fatty acid utilisation as a carbon source for anabolic synthesis of macromolecules. Here, in collaboration with the Robin Klemm group (DPAG) we shall use co-culture of fat from patient breast tissue (both involved and control non-involved breast from the same patient) with breast cancer cell lines to assess phenotypic/transcriptomic changes in both cell lines and adipocytes. Mass spectrometry will be used to trace carbon transfer from free fatty acids derived from adipocytes treated with 13C-labelled fatty acid substrates to macromolecules in tumour cells including nucleotides. Genetic silencing approaches and isogenic cell lines, based on the single sequencing data described as above will be used to identify phenotypic differences in tumour cells in obesity that may alter adipocyte behaviour and transfer of free fatty acids to aid tumour growth. Primary culture of breast tumours will be used to validate the experiments in cell lines. Complementary work will use single cell RNASeq to characterise the transcriptome of adipocytes in the tumour microenvironment and compare with adipocytes derived from a paired ‘normal’ fat sample from the non-involved breast.

Training Opportunities:

The student will be mentored via weekly one-to-one meeting with the scientific supervisor. They will regularly present their results at the Kriaucionis lab meetings, and will benefit from a range of cutting edge bioinformatics and laboratory tools and training. They will have the opportunity to gain skills in basic laboratory skills, primary tissue culture, interpretation of mass spectrometry data, and single cell sequencing. Additionally, the student will have the opportunity to develop clinical study protocols and use of human samples under supervision of Dr Lord. The candidate will spend time in the laboratory of our collaborator, Robin Klemm, to develop an understanding of novel adipocyte assays and additional knowledge of adipocyte biology (https://www.dpag.ox.ac.uk/team/robin-klemm).

 

Publications:

Lord S, Cheng W, Liu D, Gaude E, Haider S, Metcalf T, Patel N, Teoh EJ, Gleeson, F, Bradley K, Wigfield S, Zois C, McGowan D, Ah-See M, Thompson A, Sharma A, Bidaut L, Pollak M, Roy PG, Karpe F, James T, English R, Adams R, Campo L, Ayers L, Snell C, Roxanis I, Frezza C, Fenwick JD, Buffa FM, Harris AL. Integrated pharmacodynamic analysis identifies two metabolic adaption pathways to metformin in breast cancer. Cell Metabolism. 2018 Nov;28(5):679-688.

Zauri M, Berridge G, Thezenas M, Pugh KM, Goldin R, Kessler BM, Kriaucionis S. CDA directs metabolism of epigenetic nucleosides revealing a therapeutic window in cancer. Nature. 2015 Aug;524(7563):114-118