FindAPhD Weekly PhD Newsletter | JOIN NOW FindAPhD Weekly PhD Newsletter | JOIN NOW

Prostate cancer signalling to the bone micro-environment - from molecular characterization to potential novel therapies.


   Department of Oncology and Metabolism

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

About the Project

About the Project

Prostate cancer is responsible for over 52,000 cancer diagnoses within the UK per annum, and is the most common cancer in males, accounting for 27% of all new cancer cases diagnosed within men in 2016-2017. Metastatic spread of prostate cancer to bone is observed in over 80% of advanced prostate cancer patients and at this point the disease is considered incurable. Prostate cancer bone lesions typically involve the deposition of new bone, however the new bone laid down has a weaker structure leading to an increased risk of bone fractures. Treatments for prostate cancer bone metastases are currently palliative. There is considerable evidence that the tendency of prostate cancer to metastasize to bone involves communication between incoming prostate cancer cells and the cells of the bone micro-environment, creating a pre-metastatic niche. Thus the early events within prostate cancer progression, involving cell-cell communication, are pivotal targets for potential drug-based intervention.

Research at the Sheffield Bone Biomarkers Group aims to characterize the mechanisms underlying cancer spread to the skeleton within the major bone metastatic cancers, including breast, prostate and lung cancer. We have recently demonstrated the key role of prostate cancer-derived signalling vesicles (exosomes) and in particular micro-RNAs, in the priming of the pre-metastatic niche within bone in prostate cancer.   

The Sheffield Bone biomarkers group is well-placed, as part of the Mellanby Centre for Musculoskeletal Research to pursue research into bone metastatic cancers, 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 involving the University of Sheffield and the Mellanby Centre, as well as via academic collaborators.

The PhD’s objective will be to elucidate the cell-signalling alterations which occur during prostate cancer spread to bone. 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 employ a recently developed micro-RNA tracking technology as well as protein over-expression techniques, and proteomic analysis to probe the molecular mechanisms underlying prostate cancer spread to the skeleton:

Work Stream 1:

We have developed a method for affinity capture of newly synthesized proteins which enables the quantification of proteins secreted by cells without the requirement for serum-starvation of cells. The proteins expressed and secreted from two complimentary panels of prostate cancer cells will be identified and quantified. Both of these prostate cancer cell panels have represent differing stages of prostate cancer development, including the acquisition of bone-homing properties. This will identify the key signalling components differentially secreted as prostate cancer cells acquire bone-homing ability. 

Work Stream 2:

Micro-RNAs identified using our novel RNA-tracking technology will be screened using a stable-hairpin library of shRNAs to generate a cell-line panel each mimicking the action of a key micro-RNA. These cell variants will be screened in vitro for their ability to support prostate cancer survival, proliferation, acquisition of stem-cell traits and promotion of cell-viability. This will identify the key functional micro-RNAs which prime the bone micro-environment to support the growth and survival of prostate cancer cells. We also have access (via collaboration) to highly specialised – and hard to obtain – samples from human bone metastases, for the validation of these protein targets.     

Work Stream 3:

Previously research within the group has already identified some of the key proteins altered within bone-resident stromal cells to form the pre-metastatic niche. Targeted over-expression of these proteins within bone-forming stromal cells will be performed, followed by in vitro cell based assays to identify the key proteins functionally important within prostate cancer spread to bone.     

Work Stream 4:

Our ongoing research is identifying the proteins which may be secreted by bone-homing prostate cancer cells. In addition, we have active research projects characterizing the protein-components of prostate cancer derived exosomes. Together with the results from the work streams listed above, a protein panel is thus being elucidated which will form the basis of a highly specific blood-based test for the prediction of bone spread of prostate cancer. We will pursue this panel in the direction of patient-derived blood-based samples via the application of targeted-mass-spectrometry approaches. Such targeted-mass spectrometry approaches enable the quantification of large protein panels in patient cohorts.

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 would be happy to work with potential students in making grant applications for pursuit of this project. In addition, students who have already secured funding are we;lcome to apply.

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.
4. Probert, C., et al., Communication of prostate cancer cells with bone cells via extracellular vesicle RNA; a potential mechanism of metastasis. Oncogene, 2019. 38(10): p. 1751-1763.
5. Brown, J.E., et al., Guidance for the assessment and management of prostate cancer treatment-induced bone loss. A consensus position statement from an expert group. J Bone Oncol, 2020. 25: p. 100311.

Email Now


PhD saved successfully
View saved PhDs