E-Poster Presentation 34th Lorne Cancer Conference 2022

Single-cell RNA sequencing identifies potential common components of the dormant tumour cell niche across metastatic tissues (#234)

James T Smith 1 2 , Alexander P Corr 1 2 , Ryan C Chai 1 2 , Weng Hua Khoo 1 2 , Tri Phan 2 3 , Paul A Baldock 1 2 4 , Peter I Croucher 1 2
  1. Bone Biology Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. Faculty of Medicine, St Vincent's Clinical School, UNSW Australia, Sydney, NSW, Australia
  3. Intravital Microscopy Laboratory, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  4. School of Medicine Sydney, University of Notre Dame Australia, Sydney, NSW, 2010

Metastases cause 90% of cancer-related deaths and commonly occur in the skeleton, brain, liver and lungs. They arise from reactivation of dormant tumour cells (DTCs) which reside in specific cellular niches. However, the precise nature of this niche remains poorly defined, and whether the same or distinct cell types are involved in DTC niches across metastasis-prone tissues is also unknown. We hypothesise that ligand-receptor mapping of single cell data could reveal cellular and molecular components of the DTC niche across different tissues.

 

We mapped the cells comprising the bone marrow compartment by scRNA-Seq. To identify a DTC niche in bone, in silico ligand-receptor mapping examined potential signalling between DTCs from myeloma, breast and prostate with each cell type within the marrow compartment. To identify candidate DTC niches in metastasis-prone tissues, ligand-receptor mapping analysis was conducted on scRNA-Seq datasets from brain, liver and lung.

 

Forty-five distinct cell types were identified within the bone compartment. Ligand-receptor interactions were most enriched between the osteoblastic lineage and myeloma, breast and prostate DTCs (adjusted-p-value 2.1x10-6, 1.1x10-21 and 1.4x10-24). Interactions with endothelial cells were also enriched; however, there was no enrichment for progenitor cell populations. Within the osteoblast lineage, the most enriched interactions for each DTC type were with Cxcl12highLeprhigh mesenchymal stromal cells (MSCs). In normal marrow, the cell most enriched for binding partners with Cxcl12highLeprhigh MSCs was C1q+ tissue-resident macrophages. The DTC transcriptomes were enriched for myeloid genes and most closely resembled the C1q+ macrophages (adjusted-p-value myeloma 1.4x10-25; breast 4.6x10-50; prostate 4.6x10-45). C1q+ macrophage populations were identified in all metastasis-prone tissues; brain (C1q+ border-associated macrophages), liver (C1q+ Kupffer cells) and lung (C1q+ interstitial macrophages).

 

We identify Cxcl12highLeprhigh MSCs as a key cellular component of the bone DTC niche. DTCs adopt a phenotype similar to that of C1q+ macrophages, which occupy this niche under physiological conditions. C1q+ macrophages occur in brain, liver and lungs, suggesting a common niche across these tissues may be exploited by DTCs.