Dataset Information

Dissecting the cellular architecture of neuroblastoma bone marrow metastasis using single-cell transcriptomics and epigenomics

ABSTRACT: The bone marrow (BM) is the third most frequent site of metastasis for solid tumors, creating an unfavorable clinical outcome. It provides a unique microenvironment that promotes growth of tumors, however, the role of different BM cells, their molecular features, and their interactions with tumor cells, are poorly defined. Here, we investigate the BM niche in neuroblastoma (NB), a pediatric cancer of the sympathetic nervous system. NB has been molecularly defined at the primary cancer site, yet, the metastatic site is poorly characterized. We performed single-cell transcriptomics (scRNA-seq) and epigenomic profiling (scATAC-seq) of BM aspirates from 11 subjects spanning three major NB subtypes: patients with MYCN amplification (MNA), ATRX mutations (ATRXmut), and cases that lack these alterations (sporadic): NB cases were then compared to five age-matched and metastasis-free BM (controls), followed by in-depth single cell analyses of tissue diversity and cell-cell interactions. We present the first map of the epigenetic and transcriptomic effects of bone marrow metastases. Our analyses demonstrate that tumor cells in the metastatic niche display plasticity that differs among NB subtypes. NB cells via cell-cell interaction signal to the bone marrow microenvironment, rewiring specifically monocytes, which exhibit M1 and M2 features, marked by activation of pro- and anti-inflammatory programs, and express tumor-promoting factors, reminiscent of tumor-associated macrophages. Our study may provide the basis for a therapeutic approach, targeting tumor-to-microenvironment interactions.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Monocyte

SUBMITTER: Christopher Gerner

LAB HEAD: Christopher Gerner

PROVIDER: PXD036979 | Pride | 2023-07-20

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	MQ_Peak.zip	Other
	MQ_Search.zip	Other
	Spender_2_Monozyten_160607_cyt_akt.raw	Raw
	Spender_2_Monozyten_160607_cyt_akt_160628061612.raw	Raw
	Spender_2_Monozyten_160607_cyt_con.raw	Raw

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Publications

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

Fetahu Irfete S IS Esser-Skala Wolfgang W Dnyansagar Rohit R Sindelar Samuel S Rifatbegovic Fikret F Bileck Andrea A Skos Lukas L Bozsaky Eva E Lazic Daria D Shaw Lisa L Tötzl Marcus M Tarlungeanu Dora D Bernkopf Marie M Rados Magdalena M Weninger Wolfgang W Tomazou Eleni M EM Bock Christoph C Gerner Christopher C Ladenstein Ruth R Farlik Matthias M Fortelny Nikolaus N Taschner-Mandl Sabine S

Nature communications 20230626 1

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 ce ...[more]

PMID: 37365178

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Project description:Neuroblastoma (NB) is a pediatric tumor with a heterogeneous presentation at diagnosis. Fifty per cent of patients present with localized disease (stage L1/L2) whereas the other half have metastatic disease (stage M), mainly involving the bone marrow (BM). In these latter patients the physical occupancy of the BM space by metastatic NB cells has been thought to be responsible for impairment of BM function. Here, based on gene expression profiles of BM resident cells obtained in a large number of stage L and stage M NB patients, as compared to gene expression profiles of BM resident cells from healthy subjects, we investigated whether the tumor growth, either at distance or locally, affected hematopoietic lineages' maturation and release of mature hematopoietic cells in the periphery (PB). Our investigation clearly demonstrated that in children with NB, regardless of the presence of metastatic cells in the BM, there was a selective impairment of erythrocyte maturation at the ortho-chromic stage. In the BM, all the other cell lineages were un-affected. The altered erythrocyte maturation resulted in a reduced amount, and increased RWD, of PB erythrocytes. In PB samples from patients with stage L disease a significant increase in the number of mature neutrophils was observed, suggesting that in these NB patients innate immunity was activated. No increase occurred in PB of stage M NB patients. Although the cause of the selective impairment of erythrocyte maturation, as well as that of the activation of innate immunity in stage L NB patients remained elusive, our observations allowed to fully refusing the tenet that BM-infiltrating NB cells affected physiological BM functions due to physical occupancy of the BM space. In addition, these findings open the way to a new area of research not only in NB and other clinically similar pediatric cancers, such as rhabdos and sarcomas, but also in adult cancers metastasizing in the BM. Looking more carefully to the BM microenvironment could help discovering novel targets for innovative therapeutic approaches.