Abstract IA015: Niche-dependent control of tumor cell dormancy

Abstract

Abstract Dormancy is an elusive and deadly component of cancers. Rare, therapy resistant cells lay dormant for decades and when reactivated cause disease progression and relapse. Eradicating dormant cancer cells is key to curing cancers yet is an unrealized goal. The skeleton remains a common location for dissemination and dormancy, yet our understanding of the cellular and molecular pathways that control dormant cancer cells in the the skeleton is limited. We hypothesized that dormant cancer cells occupy a common niche in the skeleton and this supports long-term dormancy. To test this we developed technology to identify and analyse dormant cancers cells from different cancer types and the compartment in the skeleton in which they reside. Membrane label retention was able to distinguish dormant cancer cells from reactivated cancer cells. Intravital imaging showed that dormant cancer cells were found associated with endosteal bone surface suggesting that different cancers may occupy a common niche. Single cell RNA sequencing of dormant cancer cells showed they expressed a distinct gene signature that was enriched for myeloid genes. Single cell RNA sequencing of >130,000 cells isolated from the endosteal bone compartment and the bone marrow identified 32 distinct cell clusters. Detailed transcriptional analysis facilitated construction of a map of all of the cell types/states present in the endosteal bone compartment. In silico ligand/receptor interaction mapping enabled identification of the cell types and the molecular pathways that may mediate dormant cell niche formation in vivo. Non-haemopoietic cells, particularly cells of the osteoblast lineage and endothelia cells were the most enriched for dormant cell binding partners. This was common across three different dormant tumor types. Detailed analysis of cells of the osteoblast lineage showed greatest enrichment for binding partners in LeprHigh/Cxcl12High mesenchymal cells. Further analysis of the molecular pathways that can interact with binding partners identified a number of potential molecular regulators of dormancy. For example, Gas6, which is expressed by LeprHigh/Cxcl12High mesenchymal cells, has the binding partners Axl expressed by dormant myeloma cells, Mertk in dormant breast cancer cells and Mertk and Tyro3 in dormant prostate cancer. Treatment of mice bearing myeloma cells with small molecule inhibitors of Axl reduced dormant cells and increased tumor burden suggesting the Axl/Gas6 interaction is functional important in controlling dormancy. Together these data show that single cell sequencing can be used to define the cells and molecular pathways that facilitate dormant cancer cell niche formation in the skeleton. This approach suggests that that cancer cell specific molecules interact with common molecules in the endosteal niche, including LeprHigh/Cxcl12High mesenchymal cells, to switch on common molecular pathways to control dormancy. Citation Format: Peter Croucher, Weng Hua Khoo, Ryan Chai, Alex Corr, James Smith, Qihao Ren, Paul Baldock, Michelle McDonald, Sheila Stewart, Tri G. Phan. Niche-dependent control of tumor cell dormancy [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr IA015.