SRP311532 PRJNA716104 GSE169280 Embryonic neural crest cell derivatives release pro-metastatic cues driving neuroblastoma dissemination in an avian disease model 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. Overall design: We harvested IGR-N91 cells cultivated with the hanging drop protocol for 24 hours in E8-cSGcm, E8-cDRGcm or in E15.5-mSGcm and performed whole RNASeq analyses. For each condition, the number of significantly upregulated and downregulated transcripts as compared to control medium were homogeneously distributed. Each condition is in duplicates. GSE169280 pubmed 35538114