Endocrine Abstracts

Early detection, surgery and targeted treatments have seen remarkable improvements in cancer survival. Yet for many patients, cancers still relapse in distant organs after seemingly successful treatment of primary disease. The skeleton is one of the most common sites. Multiple myeloma develops directly in bone, whereas solid tumours, including breast and prostate cancers, spread to bone, often early in the clinical course, giving rise to incurable disease. It remains unclear how cancer cells survive in a dormant state in bone before causing disease. Unfortunately, understanding of dormant cells is limited, as they are rare, hard to isolate and difficult to study. To address this we developed intravital imaging to identify and track individual cancer cells as they disseminate to the skeleton. Cancer cells colonised the skeleton, engaged in specialised niches in the endosteal bone compartment and were retained in a dormant state. These cells were reactivated by osteoclastic remodeling of the dormant cell niche. Single-cell RNAseq analysis showed dormant cells differ from reactivated cells and are re-programmed to express a unique set of genes enriched for immune-related genes in a niche-dependent manner. Dormant cells from myeloma, breast and prostate cancer adopt a common ‘myeloid’ gene signature, taking on the persona of resident cells to avoid immune detection. A single-cell map of the endosteal bone compartment and ligand-receptor dormant cell-niche mapping identified Lepr^High/Cxcl12^High mesenchymal stromal cells as key regulators of dormancy and common molecular control pathways for all three cancers. Analysis of cells from patients identified a population of myeloma cells with a similar myeloid signature and the same Lepr^High/Cxcl12^High mesenchymal cells and molecular control pathways. Together this approach is identifying pan cancer, cell and molecular mechanisms controlling dormant cancer cells in the skeleton and providing the prospect of dormancy-targeted therapies to prevent cancer development in the skeleton.