Supervisors: Bin-Zhi Qian, Lee Smith
Prostate Cancer (PC) is the most common malignancy in men in UK. Androgen deprivation therapy (ADT) is an effective treatment for initial suppression of PC progression. However, ADT resistant or hormone-refractory PC (HRPC) inevitably emerges from androgen-responsive tumors, leading to incurable disease. Despite increasing understanding of the intrinsic signaling pathways within tumor cells, it became appreciated recently that the tumor microenvironment dramatically affects the disease outcome. Studies pioneered by us together with many others indicated that macrophages, a type of innate immune cells and important component of the tumour microenvironment, play critical roles in promoting tumour progression1,2 and therapy resistance3,4. However the role of tumour microenvironment in hormonal therapy resistance has been largely overlooked.
We now have strong evidences indicating that macrophages are critical in promoting ADT resistance in vivo. Specifically, large numbers of macrophages were recruited shortly after ADT across all examined PC models in vivo. This macrophage recruitment is associated with a surprising increase in proliferation of both cancer and stromal cells. Our preliminary data also indicate that mesenchymal stem cells promote hormone refractory tumour growth. Macrophages and MSCs represent the major hematopoietic and non-hematopoietic components of the tumour microenvironment. Thus, it is likely these two components interact with each other to promote HRPC.
Furthermore, majority of the patients die of metastatic HRPC and the tissue microenvironment is distinct in metastatic site and primary tumour. Thus, it is critical to study the resistance mechanism using proper metastatic models. To this end, we have developed the first PC bone metastasis model that responds to ADT initially but develops resistance over time. Taking advantage of the strong background of the laboratory in metastasis research5–7, this novel model provides us with a unique opportunity to study specific resistance mechanism in clinically relevant bone microenvironment. We have also adopted advanced intra-vital and ex-vivo imaging techniques of bone marrow microenvironment8 to monitor the dynamic interactions of tumour and stromal cells in physiological tissue context in real-time.
Thus, in this project, we propose to investigate the complex interactions between macrophages and MSCs in primary and bone metastatic PC in HRPC progression. We will use the state-of-the-art intra-vital imaging to elucidate the cellular and molecular interaction of different cell types in tumours in vivo. We will combine novel in vivo tumour models, gene expression microarray and multi-parameter flow cytometry-based immune-phenotyping to investigate the dynamic recruitment and differentiation of macrophages and MSC and the molecular mechanisms mediate their reciprocal interaction in HRPC. Together, these works will provide novel insight into the disease mechanism and offer new therapeutic strategies to effectively treat this lethal disease.
The Little France Campus
The MRC Centre for Reproductive Health (CRH) is located on the ground floor of the Queen’s Medical Research Institute on the University of Edinburgh’s Medical Campus at Little France. The MRC CRH enjoys close collaborative links with the other Centres on the Little France Campus including the MRC Centre for Inflammation Research (MRC-CIR); the British Heart Foundation Centre of Excellence in Cardiovascular Science (BHF-CVS), the Clinical Research Imaging Centre (CRIC) and the MRC Centre for Regenerative Medicine (CRM). The campus has a thriving postgraduate community.
Applicants are expected to have a good honours degree in the sciences (biological, chemical or physical), at least UK level of 2.1 or the equivalent from non-UK universities. A Master’s degree in a relevant subject would be an advantage.
How to apply?
Please submit a CV through the Admissions Enquiries form below.
A ‘statement of purpose’/personal statement and details of 3 academic referees will also be requested.
Application deadline 15 February 2016.
Interviews are expected to take place during early March 2016, the successful applicant beginning studies in September/October 2016, providing funding has been secured.
The 3 year MRC funded studentships are open to outstanding UK science graduates wishing to pursue a career in Reproductive Health. The studentship will cover fees at the UK/EU rate and a minimum stipend as directed by the MRC.
This research project will be in direct competition with 7 other projects currently on offer at the MRC-CRH. Usually the project with the best applicant/s will be awarded the funding. The funding is available to UK graduates who can demonstrate ordinary residence in the UK as defined at through the link below.
1. Qian, B.-Z. & Pollard, J. W. Macrophage diversity enhances tumor progression and metastasis. Cell 141, 39–51 (2010).
2. Qian, B.-Z. et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475, 222–225 (2011).
3. De Palma, M. & Lewis, C. E. Macrophage regulation of tumor responses to anticancer therapies. Cancer Cell 23, 277–86 (2013).
4. Hughes, R. et al. Perivascular M2 Macrophages Stimulate Tumor Relapse after Chemotherapy. Cancer Res. 75, 3479–3491 (2015).
5. Qian, B.-Z. et al. FLT1 signaling in metastasis-associated macrophages activates an inflammatory signature that promotes breast cancer metastasis. J. Exp. Med. 212, 1433–1448 (2015).
6. Kitamura, T. et al. CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages. J. Exp. Med. 212, 1043–1059 (2015).
7. Kitamura, T., Qian, B.-Z. & Pollard, J. W. Immune cell promotion of metastasis. Nat. Rev. Immunol. 15, 73–86 (2015).
8. Kunisaki, Y. et al. Arteriolar niches maintain haematopoietic stem cell quiescence. Nature 502, 637–43 (2013).
How good is research at University of Edinburgh in Clinical Medicine?
FTE Category A staff submitted: 206.93
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