RARRES2 is involved in the “lock-and-key” interactions between osteosarcoma stem cells and tumor-associated macrophages

Abstract

Osteosarcoma (OS) is a type of tumor. Osteosarcoma stem cells (OSCs) are responsible for drug resistance, recurrence, and immunosuppression in OS. We aimed to determine the heterogeneity of OSCs and the immunosuppression mechanisms underlying the interactions between OSCs and tumor-associated macrophages (TAMs). The cell components, trajectory changes, and cell communication profiles of OS cells were analyzed by transcriptomics at the single-cell level. The intercellular communication patterns of OSCs were verified, and the role of the cell hub genes was revealed. Hub geneS are genes that play important roles in regulating certain biological processes; they are often defined as the genes with the strongest regulatory effect on differentially expressed gene sets. Moreover, various cellular components of the OS microenvironment were identified. Malignant cells were grouped, and OSCs were identified. Further regrouping and communication analysis revealed that the genes in the stemness maintenance and differentiation subgroups were involved in communication with macrophages. Key receptor–ligand pairs and target gene sets for cell communication were obtained. Transcriptome data analysis revealed the key gene RARRES2, which is involved in intercellular communication between OSCs and TAMs. In vitro studies confirmed that macrophages promote RARRES2-mediated stemness maintenance in OSCs via the TAM-secreted cytokine insulin-like growth factor 1. Patient studies confirmed that RARRES2 could be a biomarker of OS. OSCs are highly heterogeneous, and different subgroups are responsible for proliferation and communication with other cells. The IGF-RARRES2 axis plays a key role in maintaining OSC stemness through communication with TAMs.

Extracellular Interactors of the IGF System: Impact on Cancer Hallmarks and Therapeutic Approaches

“…Similar results have been recently obtained in osteosarcoma, in which coculture experiments with TAMs and osteosarcoma cells indicate a critical role of TAM-produced IGF1 in osteosarcoma stemness [80]. In this study, the authors specifically demonstrated that TAM-secreted IGF1 acts on osteosarcoma cells and up-regulates RARRES2 expression, which maintains stemness through the NF-kB pathway and promotes chemotaxis of TAMs [80].…”