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Large 1p36 deletions affecting Arid1a locus facilitate Mycn-driven oncogenesis in a new neuroblastoma model

ABSTRACT: Loss of heterozygosity (LOH) at 1p36 is a frequent chromosomal event in a broad range of human cancers with increased incidence observed in nervous system malignancies, including neuroblastoma (NBL). MYCN amplification and 1p36 deletions are highly correlated markers of tumor aggressiveness in NBL. While short distal 1p36 losses are associated with single copy MYCN tumors, larger hemizygous 1p deletions correlate with MYCN amplification, suggesting that two tumor suppressor regions exist in 1p36, a distal and proximal region, which have MYCN-independent and dependent roles. To interrogate this, we genome-edited a proximal candidate, Arid1a, a distal candidate, Chd5, and engineered a syntenic 1p36 LOH deletion in primary mouse NCCs, the likely cell of origin for NBL. Chd5 deletions were found to confer most of the pro-tumorigenic functions of 1p36 LOH in cells expressing endogenous Mycn levels. In contrast, reduced tumor latency in Mycn-driven oncogenesis significantly correlated with the loss of Arid1a. Gene expression analysis found that tumors presenting early onset display a Polycomb Repressive Complex 2 (PRC2) signature and an impaired Trp53 signaling pathway signature. Our findings delineate the tumor suppressor functions of 1p36 LOH in NBL and potentially provide critical insights for the constellation of cancers with 1p36 deletion.

ORGANISM(S): Mus musculus

PROVIDER: GSE123142 | GEO | 2019/11/28

REPOSITORIES: GEO

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Large 1p36 deletions affecting Arid1a locus facilitate Mycn-driven oncogenesis in a new neuroblastoma model

Project description:Loss of heterozygosity (LOH) at 1p36 is a frequent chromosomal event in a broad range of human cancers with increased incidence observed in nervous system malignancies, including neuroblastoma (NBL). MYCN amplification and 1p36 deletions are highly correlated markers of tumor aggressiveness in NBL. While short distal 1p36 losses are associated with single copy MYCN tumors, larger hemizygous 1p deletions correlate with MYCN amplification, suggesting that two tumor suppressor regions exist in 1p36, a distal and proximal region, which have MYCN-independent and dependent roles. To interrogate this, we genome-edited a proximal candidate, Arid1a, a distal candidate, Chd5, and engineered a syntenic 1p36 LOH deletion in primary mouse NCCs, the likely cell of origin for NBL. Chd5 deletions were found to confer most of the pro-tumorigenic functions of 1p36 LOH in cells expressing endogenous Mycn levels. In contrast, reduced tumor latency in Mycn-driven oncogenesis significantly correlated with the loss of Arid1a. Gene expression analysis found that tumors presenting early onset display a Polycomb Repressive Complex 2 (PRC2) signature and an impaired Trp53 signaling pathway signature. Our findings delineate the tumor suppressor functions of 1p36 LOH in NBL and potentially provide critical insights for the constellation of cancers with 1p36 deletion.

2019-12-01 | GSE123281 | GEO

ARID1A Loss in Neuroblastoma Promotes the Adrenergic-to-Mesenchymal Transition by Regulating Enhancer-Mediated Gene Expression [RNA-seq]

Project description:Gene mutations in components of SWI/SNF chromatin-remodeling complexes are found in approximately 20% of all human cancers, with ARID1A being the most frequently mutated subunit. In neuroblastoma, sequence alterations of ARID1A were identified in 6% of primary tumors and cell lines, and this gene is hemizygously deleted in at least 87% of cases with chromosome 1p deletion, which almost always accompanies MYCN gene amplification and is the most common deletions in high-risk subtypes of this tumor. However, the role of ARID1A haploinsufficiency in neuroblastoma pathogenesis and the mechanisms involved remain unclear. Here, we show that disruption of ARID1A homologs in a zebrafish model accelerates the onset and increases the penetrance of MYCN-driven neuroblastoma by increasing cell proliferation in the sympathoadrenal lineage. Depletion of ARID1A in human NGP neuroblastoma cells promoted the adrenergic-to-mesenchymal transition with changes in enhancer-mediated gene expression due to alterations in the genomic occupancies of two distinct SWI/SNF assemblies, BAF and PBAF. Our findings indicate that ARID1A is a haploinsufficient tumor suppressor in MYCN-driven neuroblastoma, whose depletion enhances tumor development and promotes the emergence of the more drug resistant mesenchymal cell state.

2020-07-20 | GSE134631 | GEO

ARID1A Loss in Neuroblastoma Promotes the Adrenergic-to-Mesenchymal Transition by Regulating Enhancer-Mediated Gene Expression [ChIP-seq]

2020-07-20 | GSE134626 | GEO

Large 1p36 deletions affecting Arid1a locus facilitate Mycn-driven oncogenesis in a new neuroblastoma model

Project description:Large 1p36 deletions affecting Arid1a locus facilitate Mycn-driven oncogenesis in a new neuroblastoma model

| PRJNA508091 | ENA

Large 1p36 deletions affecting Arid1a locus facilitate Mycn-driven oncogenesis in a new neuroblastoma model

Project description:Large 1p36 deletions affecting Arid1a locus facilitate Mycn-driven oncogenesis in a new neuroblastoma model

| PRJNA507631 | ENA

CHD5 inhibits metastasis of neuroblastoma

Project description:CHD5, a tumor suppressor at 1p36, is frequently lost or silenced in poor prognosis neuroblastoma (NB) and many adult cancers. The role of CHD5 in metastasis is unknown. We confirm that low expression of CHD5 is associated with stage 4 NB. Forced expression of CHD5 in NB cell lines with 1p loss inhibited key aspects of the metastatic cascade in vitro: anchorage-independent growth, migration and invasion. In vivo, formation of bone marrow and liver metastases developing from intravenously injected NB cells was delayed and decreased by forced CHD5 expression. Genome-wide mRNA sequencing revealed reduction of genes and gene sets associated with metastasis when CHD5 was overexpressed. Known metastasis-suppressing genes preferentially up-regulated in CHD5-overexpressing NB cells included PLCL1. In patient NB, low expression of PLCL1 was associated with metastatic disease and poor survival. Knock-down of PLCL1 and of p53 in IMR5 NB cells overexpressing CHD5 reversed CHD5-induced inhibition of invasion and migration in vitro. In summary, CHD5 is a metastasis suppressor in NB.

2021-09-11 | GSE183824 | GEO

MYCN induces neuroblastoma in primary neural crest cells

Project description:Neuroblastoma (NBL) is an embryonal cancer of the sympathetic nervous system (SNS) that causes 15% of pediatric cancer deaths. High-risk neuroblastoma is characterized by N-Myc amplification and segmental chromosomal gains and losses. Due to limited disease models, the etiology of neuroblastoma is largely unknown, including both the cell of origin and the majority of oncogenic drivers. We have established a novel system for studying neuroblastoma based on the transformation of neural crest cells (NCCs), the progenitor cells of the SNS, isolated from mouse embryonic day 9.5 trunk neural tube explants. Based on pathology and gene expression analysis, we report the first successful transformation of wild-type NCCs into NBL by enforced expression of N-Myc to generate phenotypically and molecularly accurate tumors that closely model human MYCN-amplified NBL. Using comparative genomic hybridization, we found that NCC-derived neuroblastoma tumors acquired copy number gains and losses that are syntenic to those observed in human MYCN-amplified neuroblastoma including 17q gain, 2p gain and loss of 1p36. When p53-compromised NCCs were transformed with N-Myc we generated primitive neuroectodermal tumors with divergent differentiation including osteosarcoma. These subcutaneous tumors were metastatic to regional lymph nodes, liver and lung. Our novel experimental approach accurately models human neuroblastoma and establishes a new system with potential to study early stages of neuroblastoma oncogenesis, to functionally assess neuroblastoma oncogenic drivers, and to characterize neuroblastoma metastasis.

2017-09-25 | GSE94914 | GEO

Genotyping of human neuroblastoma tumors

Project description:Chromosome 1p LOH was seen in one-third of cases. LOH events on chromosomes 11q and 1p were generally accompanied by copy number loss. The one exception was on chromosome 11p, where LOH in all 4 cases was accompanied by normal copy number or diploidy, implying uniparental disomy. Amplification of MYCN was also noted, and also, amplification of a second gene, ALK, in a single case. Experiment Overall Design: We analyzed paired blood and primary tumor samples from 22 children with high-risk neuroblastoma for loss of heterozygosity (LOH) and DNA copy number change.

2008-06-16 | E-GEOD-8333 | biostudies-arrayexpress

SNP array analysis of neuroblastoma tumors

2007-06-30 | GSE8333 | GEO

Expression array of peripheral neuro-ectodermal cell lines

Project description:To study differentially expressed genes in neuro-ectodermal cell lines MYCN amplification (NMA) is the most important prognostic factor in neuroblastoma (NBL) patients, however 70% of advanced stage NBL are non-NMA and lack known driving oncogenic events. Gene expression profiles (HU133plus2.0 arrays, Affymetrix) of 17 NBL and 5 peripheral neuro-ectodermal cell lines were used to identify potential subgroups of NBL cell lines with a distinct gene signature. One group of non-NMA NBL cell lines was identified with a distinct gene expression profile and characterized by high expression of AXL. AXL is a tyrosine kinase receptor which plays a role in the metastatic process of cancer. We hypothesized that AXL contributes to the metastasizing potential of non-NMA NBL and tested if AXL silencing diminishes malignant properties of high AXL expressing cell lines. AXL was silenced in two non-NMA NBL cell lines by using a lentiviral shRNA construct that was able to transduce these cell lines with >90% infection efficiency. AXL mRNA expression level was efficiently knocked-down resulting in a severe decrease of migration of AXL positive cell lines GI-M-EN and SH-EP-2, and decreased invasion of GI-M-EN. Morphologically, AXL knockdown induced more rounded cells with a loss of contact. Intracellularly, we observed induction of stress fibers (immunofluorescence F-actin) in GI-M-EN. These changes in cytoskelet were associated with decreased migration. No effects were observed for cell proliferation, apoptosis or downstream pathways. In conclusion, AXL is identified as a possible mediator of NBL metastasis. Arrays were performed with 5 different PNET cell lines, which were used as controls for 17 NBL cell lines (GSE22771)

2012-01-01 | E-GEOD-33903 | biostudies-arrayexpress

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