The role of tumour microenvironment in metastatic hormone refractory prostate cancer
Supervisor: Dr Bin-Zhi Qian
The goal of this proposal is to investigate the role of tumour microenvironment in hormone refractory prostate cancer (HRPC).
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 understanding of the intrinsic signaling pathways within tumor cells, it became appreciated recently that the tumor microenvironment dramatically affects the disease outcome. Furthermore, majority of the patients die of metastatic HRPC and the tissue microenvironment is distinct in metastatic site compared with primary tumour. Thus, it is critical to study the resistance mechanism using proper metastatic models. 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. Taking advantage of the strong background of the laboratory in metastasis research4, we have developed a novel in vivo model 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 microenvironment to monitor the dynamic interactions of tumour and stromal cells in real-time. 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 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.
- Qian, B.-Z. & Pollard, J. W. Macrophage diversity enhances tumor progression and metastasis. Cell 141, 39–51 (2010).
- Qian, B.-Z. et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475, 222–225 (2011).
- Hughes, R. et al. Perivascular M2 Macrophages Stimulate Tumor Relapse after Chemotherapy. Cancer Res. 75, 3479–3491 (2015).
- 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).