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Characterization of the molecular mechanisms of breast cancer metastasis to bone: from basic research to biomarkers


   Department of Oncology and Metabolism

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

About the Project

About the Project

Breast cancer is responsible for over 300,000 cancer diagnoses within the UK per annum, and it is estimated that one in 7 women will develop breast cancer. Metastatic spread of breast cancer to bone is observed in over 70% of advanced breast cancer patients and at this point the disease is incurable. The spread of breast cancer to the skeleton triggers alterations in bone homeostasis resulting in osteolytic bone breakdown and an increased risk of bone fractures, spinal cord compression and hypercalcaemia (termed Skeletal Related Events – SREs). The treatment of breast cancer metastasis to bone involves use of anti-resorptive agents including bisphosphonates, or the antibody-based therapy Denosumab. These treatments are not without side-effects and therefore there is a strong and pressing need for a greater understanding of the mechanisms underlying metastatic spread of breast cancer to bone, insights which will be key to developing novel drug-treatments and treatment-informing biomarkers within this major disease area.

Research at the Sheffield Bone Biomarkers Group aims to characterize the mechanisms underlying cancer spread to the skeleton as well as develop novel therapeutic targets and biomarkers. We are well-placed, as part of the Mellanby Centre for Musculoskeletal Research to pursue this research, having access to state-of-the-art animal models of bone-metastasis, cell and molecular biology facilities, proteomic (and transcriptomic) sequencing facilities and importantly, access to patient-derived samples via clinical trials conducted involving the University of Sheffield and the Mellanby Centre.

The PhD’s objective will be to elucidate the cell-signalling alterations which accompany and facilitate metastatic spread to bone, as well as the identification of the key proteins involved in the metastatic process. In order to do this four independent lines of investigation will be pursued, all aiming to address the central question of what are the key signalling events driving the metastatic process?

We will utilise state of the art models of breast cancer metastasis to bone (as well as an independently derived model of lung metastasis), applying several complimentary approaches;

Work Stream 1:

High throughput proteomic sequencing will be applied to the study of the extra-cellular vesicles (exosomes) released by bone-metastatic as well as lung-metastatic breast cancer cells. The pivotal role of exosomes in cell-cell signalling has been established, and our previous data has identified several key pathways regulated by exosomes and involved in the metastatic spread of cancer,

Work Stream 2:

The classically secreted (non-exosomal) component of cancer cells will be profiled using our pre-optimized methodology for the quantification of secreted proteins. A panel of cells with different metastatic properties (parental, bone-homing and lung-homing will be compared),

Work Stream 3:

The functional role of the differentially secreted proteins will be probed using gene silencing technology (CRISPR-gene silencing and/or stable hairpin shRNA-technology) to reduce expression of the specific proteins. These cells will be analysed for metastatic ability within model systems,   

Work Stream 4:

Via our access to highly relevant patient derived samples, we will characterize the proteins identified within the afore-mentioned projects by targeted-mass-spectrometry approaches. Targeted-mass spectrometry enables the quantification of large protein panels in patient cohorts, allowing the statistical treatment of data necessary to advance biomarker panels towards the clinic.

The student will thus generate a body of data relevant to the development of improved diagnostic and prognostic tests within patients. The Sheffield Bone Biomarkers Group encourages active collaboration and we have future project plans with groups in other academic centres to look aspects of bone metastasis including the spatial and tissue distribution characteristics of novel biomarkers. The student will play a key role in advancing this exciting research area and forging academic and industrial collaborations. Publication and dissemination of results is central to our endeavours and the student will have the opportunity to present results at both national and international research meetings. Previous experience of protein chemistry, or cell and molecular biological experience is preferable, but thorough training will be provided in areas such as proteomic analysis, bioinformatics and bio-statistical analysis as well as use of model systems of metastasis.           


Funding Notes

We are happy to work with students who are making applications for funding to provide input into the funding applications. Students who already have funding in place are welcome.

References

1. Brown, J.E., J.A. Westbrook, and S.L. Wood, Dedicator of Cytokinesis 4: A Potential Prognostic and Predictive Biomarker Within the Metastatic Spread of Breast Cancer to Bone. Cancer Inform, 2019. 18: p. 1176935119866842.
2. Westbrook, J.A., et al., CAPG and GIPC1: Breast Cancer Biomarkers for Bone Metastasis Development and Treatment. J Natl Cancer Inst, 2016. 108(4).
3. Westbrook, J.A., et al., Identification and validation of DOCK4 as a potential biomarker for risk of bone metastasis development in patients with early breast cancer. J Pathol, 2019. 247(3): p. 381-391.

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