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Human iPSC modeling recapitulates in vivo sympathoadrenal development and reveals an aberrant developmental subpopulation in familial neuroblastoma [scRNA-seq]

ABSTRACT: Pediatric malignancies, including neuroblastoma, are best understood as disorders of development. Neuroblastoma explicitly represents a failure of sympathoadrenal development. Yet, its molecular pathogenesis remains elusive. The application of an in vitro model of human sympathoadrenal development would allow for studying the normal developmental trajectory. Such a model could also interrogate the early steps toward neuroblastoma transformation utilizing genetic manipulation. However, in vitro models have thus far been unable to generate the cells of interest reliably. We developed and characterized a human in vitro pluripotent stem cell-based model via sequential single-cell RNA sequencing throughout sympathoadrenal development. We demonstrate the power of our model to study early events of the development of human neuroblastoma. We do so by identifying the differences between normal and patient-specific induced pluripotent stem cells, derived from a child with familial neuroblastoma, harboring a germline mutation in the Anaplastic Lymphoma Kinase (ALK) gene.

ORGANISM(S): Homo sapiens

PROVIDER: GSE211661 | GEO | 2023/10/16

REPOSITORIES: GEO

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Human iPSC modeling recapitulates in vivo sympathoadrenal development and reveals an aberrant developmental subpopulation in familial neuroblastoma [Bulk RNA-seq]

Project description:Pediatric malignancies, including neuroblastoma, are best understood as disorders of development. Neuroblastoma explicitly represents a failure of sympathoadrenal development. Yet, its molecular pathogenesis remains elusive. The application of an in vitro model of human sympathoadrenal development would allow for studying the normal developmental trajectory. Such a model could also interrogate the early steps toward neuroblastoma transformation utilizing genetic manipulation. However, in vitro models have thus far been unable to generate the cells of interest reliably. We developed and characterized a human in vitro pluripotent stem cell-based model via sequential single-cell RNA sequencing throughout sympathoadrenal development. We demonstrate the power of our model to study early events of the development of human neuroblastoma. We do so by identifying the differences between normal and patient-specific induced pluripotent stem cells, derived from a child with familial neuroblastoma, harboring a germline mutation in the Anaplastic Lymphoma Kinase (ALK) gene.

2023-10-16 | GSE211660 | GEO

Human iPSC modeling recapitulates in vivo sympathoadrenal development and reveals an aberrant developmental subpopulation in familial neuroblastoma

Project description:Human iPSC modeling recapitulates in vivo sympathoadrenal development and reveals an aberrant developmental subpopulation in familial neuroblastoma

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Human iPSC modeling recapitulates in vivo sympathoadrenal development and reveals an aberrant developmental subpopulation in familial neuroblastoma [scRNA-seq]

Project description:Human iPSC modeling recapitulates in vivo sympathoadrenal development and reveals an aberrant developmental subpopulation in familial neuroblastoma [scRNA-seq]

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Using human stem cell derived in vitro modeling to characterize the effect of MYCN overexpression on early hSAP development and tumor formation

Project description:In this study we use human stem cell derived in vitro modelling to characterize the effect of MYCN overexpression on early hSAP development and tumor formation. We developed and characterized a human in vitro pluripotent stem cell-based model via sequential single-cell RNA sequencing throughout sympathoadrenal development.

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Human iPSC modeling recapitulates <i>in vivo</i> sympathoadrenal development and reveals an aberrant developmental subpopulation in familial neuroblastoma.

Project description:Studies defining normal and disrupted human neural crest cell development have been challenging given its early timing and intricacy of development. Consequently, insight into the early disruptive events causing a neural crest related disease such as pediatric cancer neuroblastoma is limited. To overcome this problem, we developed an in vitro differentiation model to recapitulate the normal in vivo developmental process of the sympathoadrenal lineage which gives rise to neuroblastoma. We used human in vitro pluripotent stem cells and single-cell RNA sequencing to recapitulate the molecular events during sympathoadrenal development. We provide a detailed map of dynamically regulated transcriptomes during sympathoblast formation and illustrate the power of this model to study early events of the development of human neuroblastoma, identifying a distinct subpopulation of cell marked by SOX2 expression in developing sympathoblast obtained from patient derived iPSC cells harboring a germline activating mutation in the anaplastic lymphoma kinase (ALK) gene.

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Project description:It is proposed that the impaired sympathoadrenal response to hypoglycemia induced by recurrent insulin-induced hypoglycemia (RH) is an adaptive phenomenon induced by specific changes in microRNA expression in the ventromedial hypothalamus (VMH). To test this hypothesis, genome-wide microRNAomic profiling of the VMH by RNA-sequencing was performed in control and RH treated rats. Differential expression analysis identified microRNA-7a-5p and microRNA-665 as potential mediators of this phenomenon. To further test this hypothesis, experiments were conducted consisting of targeted lentiviral-mediated overexpression of microRNA-7a-5p and downregulation of microRNA-665 in the VMH. Hyperinsulinemic hypoglycemic clamp experiments demonstrated that targeted overexpression of microRNA-7a-5p (but not downregulation of microRNA-665) in the VMH of RH rats restored the epinephrine response to hypoglycemia. This restored response to hypoglycemia was associated with a restoration of GABAA receptor gene expression. Finally, a direct interaction of microRNA-7a-5p with 3’-UTR of GABAA receptor α1-subunit (Gabra1) gene was demonstrated in a luciferase assay. These findings indicate that 1) the impaired sympathoadrenal response induced by RH is associated with changes in VMH microRNA expression, and 2) microRNA-7a-5p, possibly via direct downregulation of GABA receptor gene expression, may serve as a mediator of the altered sympathoadrenal response to hypoglycemia.

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Human iPSC modeling recapitulates in vivo sympathoadrenal development and reveals an aberrant developmental subpopulation in familial neuroblastoma

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-10-16 | GSE211664 | GEO

Silencing of the PHLDA1 leads to global proteome changes and differentiation pathways of human neuroblastoma cells

Project description:Neuroblastoma (NB) is the most common extracranial pediatric solid tumor originating from the abnormal development of cells of the sympathoadrenal lineage of the neural crest. Targeting GD2 ganglioside (GD2), a glycolipid expressed on neuroblastoma cells, with GD2 ganglioside-recognizing antibodies affects several pivotal signaling routes that drive or influence the malignant phenotype of the cells. Previously performed gene expression profiling helped us to identify the PHLDA1 (pleckstrin homology-like domain family A member 1) gene as the most upregulated gene in the IMR-32 human neuroblastoma cells treated with the mouse 14G2a monoclonal antibody. Mass spectrometry-based proteomic analyses were applied to better characterize a role of PHLDA1 protein in the response of neuroblastoma cells to chimeric ch14.18/CHO antibody. Additionally, global protein expression profile analysis in the IMR-32 cell line with PHLDA1 silencing revealed increase in biological functions of mitochondria, accompanied by differentiation-like phenotype of the cells. Moreover, mass spectrometry analysis of the proteins co-immunoprecipitated using anti-PHLDA1-specific antibody, selected a group of possible PHLDA1 binding partners. Also, a more detailed analysis suggested that PHLDA1 interacts with the DCAF7/AUTS2 complex, a key component of neuronal differentiation in vitro.

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