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Embryonic neural crest cell derivatives release pro-metastatic cues driving neuroblastoma dissemination in an avian disease model

ABSTRACT: Embryonic malignant transformation is concomitant to organogenesis, often affecting multipotent and migratory progenitors. Neuroblastoma (NB) is an emblematic example, arising from neural crest progenitors and characterized by a high heterogeneity and a widely disseminated clinical presentation. Metastatic triggers from the embryonic environment are suspected but yet unknown due to limited investigation access in patients and current models. Using combinations of ex vivo and in vivo models mimicking the embryonic context coupled to proteomic and transcriptomic analyses, we identify Olfactomedin1 (OLFM1) released by sympathetic derivatives at the core of a gene program promoting NB cells decohesion, primary tumor escape and dissemination. This OLFM signature discriminates metastatic from localized stages in NB patient cohorts. Finally, we report an extended tumor cell escape gene signature of disseminated forms specifically shared by cancers with neural-crest origin, revealing a sustained embryonic imprint of the lineage of origin, manifested in the metastatic properties of malignant cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE169280 | GEO | 2022/03/09

REPOSITORIES: GEO

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Project description:This GEO series contains human scRNA-seq data of Neuroblastoma patients, used in two manuscripts. n=7 paired samples, primary tumour vs. bone marrow metastases n=2 non-paired samples, bone marrow metastases Titles: Article 1 PUBLISHED: Neuroblastoma plasticity during metastatic progression stems from the dynamics of an early sympathetic transcriptomic trajectory See Citation and PubMed ID below. Article 2 UNDER REVIEW: Single-cell analyses of paired primary neuroblastoma tumor and bone marrow metastases reveals intra-patient heterogeneity and therapy-resistant subpopulations Abstract of article 1: Despite their indisputable importance in neuroblastoma (NB) pathology, knowledge of the bases of NB plasticity and heterogeneity remains incomplete. They may be rooted in developmental trajectories of their lineage of origin, the sympatho-adrenal neural crest. We found that implanting human NB cells in the neural crest of the avian embryo allows recapitulating the metastatic sequence until bone marrow involvement. Using deep single cell RNA sequencing, we characterized transcriptome states of NB cells and their dynamics over time and space, and compared them to those of fetal sympatho-adrenal tissues and patient tumors and bone marrow samples. Here we report remarkable transcriptomic proximities restricted to an early sympathetic neuroblast branch that co-exist with phenotypical adaptations over disease progression and recapitulate intratumor and interpatient heterogeneity. Combining avian and patient datasets, we identified a list of genes upregulated upon bone marrow involvement and associated with growth dependency, validating the relevance of our multimodal approach. Despite being key pathological features, Neuroblastoma (NB) plasticity and Heterogeneity remain largely misunderstood. They may be rooted in complex developmental trajectories of their embryonic lineage of origin, the sympatho-adrenal neural crest. We found that implanting human NB cells in the neural crest of the avian embryo allows recapitulating the metastatic sequence until bone marrow involvement. Using deep single cell RNA sequencing, we characterized transcriptional states of NB cells and their dynamics over time and space, and compared them to those of fetal sympatho-adrenal tissues and patient tumors, including matched primary tumor and bone marrow samples. We found remarkable transcriptomic proximities restricted to an early sympathetic neuroblast branch that co-exist with phenotypical adaptations over disease progression and recapitulate intratumor and interpatient heterogeneity. Combining avian model and patient datasets, we identified a list of candidate genes upon bone marrow involvement associated with NB growth dependency, validating the relevance of our multimodal approach.

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Embryonic neural crest cell derivatives release pro-metastatic cues driving neuroblastoma dissemination in an avian disease model

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