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Credentialling a c-MYC-driven genetic neuroblastoma model [RNAseq-NB]

ABSTRACT: Credentialling a c-MYC-driven genetic neuroblastoma model [RNAseq-NB]

PROVIDER: PRJNA1073948 | ENA |

REPOSITORIES: ENA

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Credentialling a c-MYC-driven genetic neuroblastoma model [RNAseq-NB]

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Project description:High-risk neuroblastoma (NB) often involves amplification of the neural MYC (MYCN) oncogene as well as mutations in ALK. Currently, high-risk NB presents significant clinical challenges, and additional therapeutic options are needed. Oncogenes such as MYCN and ALK result in increased replication stress in cancer cells, offering one such therapeutically exploitable option. Here, we followed up on earlier phosphoproteomic analyses that identified ATR activity in ALK-driven NB cell lines. We tested several ATR inhibitors, identifying BAY 1895344 as the most potent inhibitor of NB cell growth and proliferation. Using RNA-Seq, proteomics and phosphoproteomics we characterized the response of NB cells and tumours to ATR inhibition, identifying key components of the DNA damage response (DDR) as well as ATRX, MYCN, E2F and DCK among other ATR targets in NB cells. ATR inhibition with BAY 1895344 also produced robust responses in mouse NB models. Remarkably, a 2 week protocol combining ATR and ALK inhibition led to complete regression of NB tumours in two independent NB genetically modified mouse tumour models. These results suggest that NB patients, particularly in high-risk groups with oncogene induced replication stress, may benefit from inhibition of ATR as therapeutic intervention.

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Genome-wide profiling of mature piRNAs in human Neuroblastoma (NB) cell lines

Project description:To elucidate potential role of piRNAs in Neuroblastoma (NB), we performed the genome wide profiling in two human NB cell lines, IMR-32 and SH-SY-5Y by adopting high-throughput RNA sequencing (RNA-Seq) and unveil their possible functions in neoplastic pathways. The RNA sequencing results revealed both known and novel piRNAs in both the cell lines. We observed a total 630 annotated mature piRNAs, distributed across chromosomes and mitochondria which were mapped to various genomic locations such as introns, protein coding regions, repeats, pseudogenes, ncRNAs etc. This is the first study reporting the extensive catalogue of human NB piRNAs which will provide a useful resource to dissect complex neoplastic events that are possibly mediated by piRNAs in neuroblastoma. Moreover, these piRNAs could be used as probable small RNA biomarkers for the Neuroblastoma.

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Transcription profiling of mouse NB N1E-115 cells with wildtype, overexpression, knockdown of neuroblastoma Tcof1

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