Neuroblastoma plasticity during metastatic progression stems from the dynamics of an early sympathetic transcriptomic trajectory.

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 find 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 characterize transcriptome states of NB cells and their dynamics over time and space, and compare 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 identify a list of genes upregulated during bone marrow involvement and associated with growth dependency, validating the relevance of our multimodal approach.

Environmental cues from neural crest derivatives act as metastatic triggers in an embryonic neuroblastoma model.

Embryonic malignant transformation is concomitant to organogenesis, often affecting multipotent and migratory progenitors. While lineage relationships between malignant cells and their physiological counterparts are extensively investigated, the contribution of exogenous embryonic signals is not fully known. Neuroblastoma (NB) is a childhood malignancy of the peripheral nervous system arising from the embryonic trunk neural crest (NC) and characterized by heterogeneous and interconvertible tumor cell identities. Here, using experimental models mimicking the embryonic context coupled to proteomic and transcriptomic analyses, we show that signals released by embryonic sympathetic ganglia, including Olfactomedin-1, induce NB cells to shift from a noradrenergic to mesenchymal identity, and to activate a gene program promoting NB metastatic onset and dissemination. From this gene program, we extract a core signature specifically shared by metastatic cancers with NC origin. This reveals non-cell autonomous embryonic contributions regulating the plasticity of NB identities and setting pro-dissemination gene programs common to NC-derived cancers.

An avian embryo patient-derived xenograft model for preclinical studies of human breast cancers.

Lack of preclinical patient-derived xenograft cancer models in which to conduct large-scale molecular studies seriously impairs the development of effective personalized therapies. We report here an in vivo concept consisting of implanting human tumor cells in targeted tissues of an avian embryo, delivering therapeutics, evaluating their efficacy by measuring tumors using light sheet confocal microscopy, and conducting large-scale RNA-seq analysis to characterize therapeutic-induced changes in gene expression. The model was established to recapitulate triple-negative breast cancer (TNBC) and validated using TNBC standards of care and an investigational therapeutic agent.

Draft genome sequences for three unisolated Alnus-infective Frankia Sp+ strains, AgTrS, AiOr and AvVan, the first sequenced Frankia strains able to sporulate in-planta.

Actinobacteria from genus Frankia are able to form symbiotic associations with actinorhizal plants including alders. Among them, Sp+ strains are characterized by their ability to differentiate numerous sporangia inside host plant cells (unlike "Sp-" strains unable of in-planta sporulation). Here, we report the first genome sequences of three unisolated Sp+ strains: AgTrS, AiOr and AvVan obtained from Alnus glutinosa, A. incana and A. alnobetula (previously known as viridis), respectively (with genome completeness estimated at more than 98%). They represent new Frankia species based on Average Nucleotide Identity (ANI) calculations, and the smallest Alnus-infective Frankia genomes so far sequenced (~5 Mbp), with 5,178, 6,192 and 5,751 candidate protein-encoding genes for AgTrS, AiOr and AvVan, respectively.