Plasticity in Neuroblastoma Cell Identity Defines a Noradrenergic-to-Mesenchymal Transition (NMT).
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ABSTRACT:
SUBMITTER: Gautier M
PROVIDER: S-EPMC8230375 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Noradrenergic and mesenchymal identities have been characterized in neuroblastoma cell lines according to their epigenetic landscapes and core regulatory circuitries. However, their relationship and relative contribution in patient tumors remain poorly defined. We now document spontaneous and reversible plasticity between the two identities, associated with epigenetic reprogramming, in several neuroblastoma models. Interestingly, xenografts with cells from each identity eventually harbor a noradrenergic phenotype suggesting that the microenvironment provides a powerful pressure towards this phenotype. Accordingly, such a noradrenergic cell identity is systematically observed in single-cell RNA-seq of 18 tumor biopsies and 15 PDX models. Yet, a subpopulation of these noradrenergic tumor cells presents with mesenchymal features that are shared with plasticity models, indicating that the plasticity described in these models has relevance in neuroblastoma patients. This work therefore emphasizes that intrinsic plasticity properties of neuroblastoma cells are dependent upon external cues of the environment to drive cell identity.
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Project description:Pleiotropic genetic factors (e.g., DNA polymorphisms) may be involved in the initiation of neuroblastoma (NB) and coronary artery disease (CAD) given their common origin from defects in neural crest development. To discover novel NB susceptibility genes, we conducted a three-stage survey including a meta-analysis of NB and CAD genome-wide association data, prioritization of NB causal variants, and validation in an independent cohort of affected individuals-control subjects. The lead SNP, rs13337397 at the 16q23.1 locus, associated with both diseases in the meta-analysis and with NB in the validation study. All the SNPs in linkage disequilibrium with rs13337397 were annotated using the H3K27ac epigenetic marker of neural crest cells (NCC) and NB cell lines. Indeed, we identified the functional SNP rs13337017, mapping within an enhancer of NCCs and NB cell lines and showing long-range interactions with CFDP1 by Hi-C analysis. Luciferase assays indicated that the risk allele of rs13337017 increased CFDP1 expression in NB cell lines. Of note, CFDP1 high expression associated with unfavorable prognostic markers in an analysis including 498 NB transcriptomes. Moreover, depletion of CFDP1 markedly decreased viability and migration and increased apoptotic rates in NB cell lines. Finally, transcriptome and qPCR analyses revealed that the depletion of CFDP1 may affect noradrenergic neuron differentiation by downregulating master regulators of sympathetic noradrenergic identity, including PHOX2B, HAND2, and GATA3. Our data strongly suggest that CFDP1 acts as oncogene in NB. In addition, we provide evidence that genetic predisposition to NB can be mediated by the alteration of noradrenergic lineage-specific gene expression.
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Project description:Aberrant activation of anaplastic lymphoma kinase (ALK) drives neuroblastoma (NB). Previous work identified the RET receptor tyrosine kinase (RTK) as a downstream target of ALK activity in NB models. We show here that ALK activation in response to ALKAL2 ligand results in the rapid phosphorylation of RET in NB cells, providing additional insight into the contribution of RET to the ALK-driven gene signature in NB. To further address the role of RET in NB, RET knockout (KO) SK-N-AS cells were generated by CRISPR/Cas9 genome engineering. Gene expression analysis of RET KO NB cells identified a reprogramming of NB cells to a mesenchymal (MES) phenotype that was characterized by increased migration and upregulation of the AXL and MNNG HOS transforming gene (MET) RTKs, as well as integrins and extracellular matrix components. Strikingly, the upregulation of AXL in the absence of RET reflects the development timeline observed in the neural crest as progenitor cells undergo differentiation during embryonic development. Together, these findings suggest that a MES phenotype is promoted in mesenchymal NB cells in the absence of RET, reflective of a less differentiated developmental status.
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Project description:Pleiotropic genetic factors (e.g., DNA polymorphisms) may be involved in the initiation of neuroblastoma (NB) and coronary artery disease (CAD) given their common origin from defects in neural crest development. To discover novel NB susceptibility genes, we conducted a three-stage survey including a meta-analysis of NB and CAD genome-wide association data, prioritization of NB causal variants, and validation in an independent case-controls cohort. The lead SNP, rs13337397 at the 16q23.1 locus, associated with both diseases in the meta-analysis and with NB in the validation study. All the SNPs in linkage disequilibrium with rs13337397 were annotated using the H3K27ac epigenetic marker of neural crest cells (NCC) and NB cell lines. Indeed, we identified the functional SNP rs13337017, mapping within an enhancer of NCCs and NB cell lines and showing long-range interactions with CFDP1 by Hi-C analysis. Luciferase assays indicated that the risk allele of rs13337017 increased CFDP1 expression in NB cell lines. Of note, CFDP1 high expression associated with unfavorable prognostic markers in an analysis including 498 NB transcriptomes. Moreover, depletion of CFDP1 markedly decreased viability and migration and increased apoptotic rates in NB cell lines. Finally, transcriptome and qPCR analyses revealed that the depletion of CFDP1 may affect noradrenergic neuron differentiation by downregulating master regulators of sympathetic noradrenergic identity, including PHOX2B, HAND2 and GATA3. Our data strongly suggest that CFDP1 acts as oncogene in NB. Additionally, we provide evidence that genetic predisposition to NB can be mediated by the alteration of noradrenergic lineage-specific gene expression.
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Project description:Aberrant activation of Anaplastic Lymphoma Kinase (ALK) drives neuroblastoma (NB). Previous work has identified the RET receptor tyrosine kinase (RTK) as a downstream target of ALK activity in NB models. We show here that ALK activation in response to ALKAL2 ligand results in the rapid phosphorylation of RET in NB cells, providing additional insight into the contribution of RET to the ALK driven gene signature in NB. To further address the role of RET in NB, RET knock-out (KO) SK-N-AS cells were generated by CRISPR/Cas9 genome engineering. Gene expression analysis of RET KO NB cells identified a reprogramming of NB cells to a mesenchymal (MES) phenotype that was characterized by increased migration and upregulation of the AXL and MET RTKs as well as integrins and extracellular matrix components. Strikingly, the upregulation of AXL in the absence of RET reflects the development timeline observed in the neural crest as progenitor cells undergo differentiation during embryonic development. Together, these findings suggest that a MES phenotype is promoted in mesenchymal NB cells in the absence of RET, reflective of a less differentiated developmental status.
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