Prostate cancer (PCa) is the most common non-cutaneous malignancy in men and accounts for 360,000 deaths each year worldwide. Bone metastases are present in approximately 90% of men with advanced PCa and are associated with debilitating skeletal symptoms and shortened survival. Tumour cells can be detected in the bone marrow of patients with localised PCa and, despite local therapy with curative intent, a significant number of those patients will relapse with lethal bone metastases several years later. This suggests that a subset of tumour cells can persist in the bone marrow in a dormant state, primed for reactivation. It has been shown that metastatic PCa cells specifically target the osteoblast- rich endosteal niche in bone marrow. However, the mechanisms underlying osteoblast-PCa cell interactions and the signalling pathways regulating tumour cell survival and dormancy in bone are not fully defined. The aim of this study was to characterise osteoblast-regulated phenotypes and signalling pathways in PCa cells using cytokine profiling and phosphoproteomics, with the goal of identifying novel approaches to therapeutically target dormant cells. Using this approach, it was observed that conditioned medium (CM) from mature osteoblasts differentially affected the growth of various PCa cell lines and regulated key phenotypes related to metastasis. In C4-2B cells, interleukin-6 (IL-6) - abundant in mature osteoblast CM - suppressed growth and induced autophagy as a survival mechanism in growth-arrested, dormant-like cells. Following a period of growth arrest, the majority of C4-2B cells underwent apoptosis driven by the stress-activated kinase p38. However, a subset survived to establish colonies upon the removal of growth-inhibitory CM, potentially representing a putative dormancy-prone population. Phosphoproteomics identified the p38 substrate TRIM28 as a protein promoting survival by limiting apoptosis in PCa cells and levels of TRIM28 were correlated with disease progression in clinical cohorts. It is proposed that the balance between p38-driven apoptotic cell death and survival via IL-6-driven autophagy contributes to dormancy in PCa cells. While these findings require validation in more clinically relevant PCa models, this study highlights a potential opportunity to target dormant cells using autophagy inhibitors already in the clinic. Ultimately, this may provide significant clinical benefit for patients by preventing or delaying disease relapse in bone.
|Date of Award
|1 Aug 2020
- The University of Manchester
|Paul Townsend (Supervisor) & Berna Sayan (Supervisor)