Single-cell transcriptomics and epigenomics unravel the role of monocytes in neuroblastoma bone marrow metastasis

• Published in: Nature communications Vol. 14; no. 1; pp. 3620 - 17
• Main Authors: Fetahu, Irfete S., Esser-Skala, Wolfgang, Dnyansagar, Rohit, Sindelar, Samuel, Rifatbegovic, Fikret, Bileck, Andrea, Skos, Lukas, Bozsaky, Eva, Lazic, Daria, Shaw, Lisa, Tötzl, Marcus, Tarlungeanu, Dora, Bernkopf, Marie, Rados, Magdalena, Weninger, Wolfgang, Tomazou, Eleni M., Bock, Christoph, Gerner, Christopher, Ladenstein, Ruth, Farlik, Matthias, Fortelny, Nikolaus, Taschner-Mandl, Sabine
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26.06.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/21; 13/31; 14/1; 14/63; 38/39; 42/47; 631/337/100/101; 631/337/176; 631/337/2019; 631/67/327; 631/67/68; 82/79; 82/80; Bone cancer; Bone marrow; Bone Marrow - pathology; Bone Marrow Neoplasms - genetics; Bone Marrow Neoplasms - metabolism; Bone Marrow Neoplasms - pathology; Cancer; Cell interactions; Child; Children; Epigenomics; Humanities and Social Sciences; Humans; Inflammation; Macrophages; Metastases; Metastasis; Microenvironments; Midkine; Monocytes; Monocytes - metabolism; multidisciplinary; Neuroblastoma; Neuroblastoma - metabolism; Plastic foam; Plastic properties; Plasticity; Science; Science (multidisciplinary); Tissue analysis; Transcriptome; Transcriptomics; Tumor cells; Tumor Microenvironment - genetics; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-39210-0

Metastasis is the major cause of cancer-related deaths. Neuroblastoma (NB), a childhood tumor has been molecularly defined at the primary cancer site, however, the bone marrow (BM) as the metastatic niche of NB is poorly characterized. Here we perform single-cell transcriptomic and epigenomic profiling of BM aspirates from 11 subjects spanning three major NB subtypes and compare these to five age-matched and metastasis-free BM, followed by in-depth single cell analyses of tissue diversity and cell-cell interactions, as well as functional validation. We show that cellular plasticity of NB tumor cells is conserved upon metastasis and tumor cell type composition is NB subtype-dependent. NB cells signal to the BM microenvironment, rewiring via macrophage mgration inhibitory factor and midkine signaling specifically monocytes, which exhibit M1 and M2 features, are marked by activation of pro- and anti-inflammatory programs, and express tumor-promoting factors, reminiscent of tumor-associated macrophages. The interactions and pathways characterized in our study provide the basis for therapeutic approaches that target tumor-to-microenvironment interactions. The bone marrow is a common site of metastasis for neuroblastoma patients. Here, the authors perform single cell RNA-seq and ATAC-seq of bone marrow aspirates from 16 subjects and show conservation of tumor cell plasticity in metastases and identify tumor-to-bone marrow cell signals that trigger tumor promoting monocytes.