Oral Presentation 29th Australian and New Zealand Bone and Mineral Society Annual Scientific Meeting 2019

Single Cell Ligand-Receptor Mapping of the Endosteal Bone Niche Identifies Regulators of Tumour Cell Dormancy (#56)

Alexander P Corr 1 2 , Ryan C Chai 1 , Weng Hua Khoo 1 , Matthew A Summers 1 2 , John A Eisman 1 2 3 , Paul A Baldock 1 2 3 , Peter I Croucher 1 2
  1. Bone Biology Group, Cancer Plasticity and Dormancy Program, Garvan Institute of Medical Research, Sydney, NSW, Australia
  2. School of Clinical Medicine, Faculty of Medicine and Health, UNSW, Sydney, NSW, Australia
  3. School of Medicine Sydney, University of Notre Dame Australia, Sydney, NSW, Australia

In many cancers, recurrent bone metastases represent a leading cause of morbidity and mortality. Metastatic relapse can occur years after seemingly successful treatment of the primary disease due to the dissemination and reactivation of therapy-resistant dormant tumour cells (DTCs) in the bone microenvironment. Critically, little is known about the molecular programs governing tumour cell dormancy and the role played by the bone microenvironment in establishing and maintaining cancer cells in this state. We hypothesised that distinct cell-types within the endosteal niche control DTCs via specific ligand-receptor interactions. These interactions were modelled using a single cell sequencing (scRNA-seq) approach. 

We sequenced the transcriptomes of 36 dormant and 43 active 5TGM1 murine myeloma cells using the SMART-Seq platform and identified genes upregulated during dormancy by differential expression analysis. scRNA-seq was also performed on 133,942 individual cells of the bone microenvironment, including the endosteal niche using the 10x Chromium system. An in silico ligand-receptor screen was employed to model interactions between DTCs and cells of the endosteal niche. This analysis identified 214 DTC-niche potential interactions. Osteoblastic cells expressed the most DTC-niche interaction partners (29 pairs), with macrophages (25) and endothelial cells (22) also exhibiting crosstalk potential. High-resolution mapping of the osteoblast lineage identified CXCL12-abundant reticular (CAR) cells as most enriched for DTC-niche interactions (14 pairs). Among the top-ranking CAR cell interactions was Axl-Gas6 which, when inhibited in vivo, released tumour cells from dormancy. The analysis also identified several other interaction partners that have yet to be considered in the context of controlling tumour cell dormancy.

This study utilised single cell transcriptional data to model intercellular ligand-receptor communication between DTCs and the endosteal bone niche. The resulting network predicted DTC-osteoblast crosstalk as a key regulator of tumour cell dormancy and identified novel therapeutic targets as candidates to prevent recurrence of skeletal metastases.