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

Author:

Fetahu Irfete S.ORCID,Esser-Skala Wolfgang,Dnyansagar Rohit,Sindelar Samuel,Rifatbegovic FikretORCID,Bileck AndreaORCID,Skos LukasORCID,Bozsaky EvaORCID,Lazic Daria,Shaw LisaORCID,Tötzl MarcusORCID,Tarlungeanu Dora,Bernkopf MarieORCID,Rados Magdalena,Weninger Wolfgang,Tomazou Eleni M.ORCID,Bock ChristophORCID,Gerner ChristopherORCID,Ladenstein RuthORCID,Farlik MatthiasORCID,Fortelny NikolausORCID,Taschner-Mandl SabineORCID

Abstract

AbstractMetastasis 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.

Funder

Vienna Science and Technology Fund

Austrian Science Fund

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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