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

Abstract

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 in vivo avian model of human melanoma to perform rapid and robust preclinical studies

“…In addition, we could model synergistic/antagonistic behaviors of combination of targeted therapies depending on melanoma cell phenotypes, underlining the power of our in vivo paradigm to provide relevant information on the efficacy of candidate molecules, even in complex therapeutic regimens. Longer treatments were not experienced in this study but are compatible with the AVI‐PDX TM (Ben Amar et al , 2022) and could help addressing other questions, such as responses to sequential therapies or effects on metastatic extension. Overall, we provide proof‐of‐concept that the AVI‐PDX TM model accurately reproduces melanoma patient response to BRAFi/MEKi, and is highly suited to assess the efficacy of drug combinations.…”

“…Sample size (number of grafted embryos) for patient samples was not estimated as the total and limited amount of material available was used. For engraftment of cell lines, sample size was not estimated using statistical methods but was rather based on previous studies using avian embryos (Delloye‐Bourgeois et al , 2017; Jarrosson et al , 2021; Ben Amar et al , 2022).…”

Oxytocin accelerates tight junction formation and impairs cellular migration in 3D spheroids: evidence from Gapmer-induced exon skipping

“…This process is of special interest for the treatment of degenerative diseases where cells lose polarity, cell-cell contacts, and undergo apoptosis, e.g., as it is the case in the breakdown of the blood-brain barrier (Knox et al, 2022 ). Another pathological aspect that is affected by cell-cell contacts and cell polarity is metastatic tumor formation, where single cells undergo EMT, detach from the primary tumor, and invade other organs or tissues via the bloodstream (Ben Amar et al, 2022 ). As OXT opposes the EMT by inducing the formation of tight junctions and also inhibits cellular migration, it might be helpful to consider its use as an adjuvant treatment.…”

Patient-derived models: Advanced tools for precision medicine in neuroblastoma

“…Treatment resistance, relapse after therapy, and metastasis are urgent clinical problems in NB. A few studies have used PD models to identify diverse mechanisms implicated in NB invasion, migration, metastasis ( 64 , 65 ), and resistance to specific chemotherapies ( 66 ). Using a clinically relevant treatment protocol (COJEC-induction therapy), NB PDXs show similar chemotherapy responses to their corresponding patients, suggesting that NB PDXs are useful for modelling chemoresistance and relapse ( 46 ).…”