Single-cell transcriptomics and epigenomics unravel the role of monocytes in neuroblastoma bone marrow metastasis
Irfete S. Fetahu, Wolfgang Esser‐Skala, Rohit Dnyansagar, Samuel Sindelar, Fikret Rifatbegovic, Andrea Bileck, Lukas Skos, Eva Bozsaky, Daria Lazic, Lisa E. Shaw, Marcus Tötzl, Dora Tarlungeanu, Marie Bernkopf, Magdalena Radoš, Wolfgang Weninger, Eleni M. Tomazou, Christoph Bock, Christopher Gerner, Ruth Ladenstein, Matthias Farlik, Nikolaus Fortelny, Sabine Taschner‐Mandl
Abstract
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.