Applications are invited from outstanding candidates to join a Cancer Research UK funded PhD programme at the Cancer Research UK Edinburgh Centre, part of the MRC Institute of Genetics and Molecular Medicine (IGMM) at the University of Edinburgh.
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 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 progression and therapy resistance. However the role of tumour microenvironment in hormonal therapy resistance has been largely overlooked.
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 but develops resistance over time. Taking advantage of the strong background of the laboratory in metastasis research, this novel model provides us with a unique opportunity to study specific resistance mechanism in clinically relevant bone microenvironment.
Thus, in this project, we propose to investigate the complex interactions between macrophages and MSCs in bone metastatic PC in disease 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 profiling 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 mHRPC. Together, these works will provide novel insight into the disease mechanism and offer new therapeutic strategies to effectively treat this lethal disease.