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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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RNA-seq of neuroblastoma mouse model (Alk-F1178S;Th-MYCN) after treatment with the ATR inhibitor ceralasertib

ABSTRACT: To understand the in vivo transcriptomic response to ATR inhibition, RNA-Seq was performed 3 days after treatment of a previously developed neuroblastoma mouse model (Alk-F1178S;Th-MYCN; see Borenas et al., EMBO J, 2021) with the ATR inhibitor ceralasertib.

INSTRUMENT(S): Illumina NovaSeq 6000

ORGANISM(S): Mus musculus

SUBMITTER: Jimmy Van den Eynden

PROVIDER: E-MTAB-12961 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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RNA-seq of neuroblastoma mice models after treatment with the ATR inhibitor BAY 1895344

Project description:To understand the in vivo transcriptomic response to ATR inhibition, RNA-Seq was performed after treatment of 2 previously developed neuroblastoma mouse models (Alk-F1178S;Th-MYCN and Rosa26_Alkal2;Th-MYCN; see Borenas et al., EMBO J, 2021) with the ATR inhibitor BAY 1895344.

2021-10-21 | E-MTAB-10616 | biostudies-arrayexpress

RNA-seq of TH-MYCN driven neuroblastoma mice +/- ALK F1178S mutation and +/- ALKAL2 overexpression

Project description:ALK is a tyrosine kinase receptor and oncogene in neuroblastoma (NB). The receptor is activated by the ALKAL2 ligand, but it is unknown whether missregulation of this ligand may play a role in NB carcinogenesis. Here, a TH-MYCN driven neuroblastoma mice was created +/- ALK F1178S mutation and +/- ALKAL2 overexpression

2020-11-24 | E-MTAB-9600 | biostudies-arrayexpress

Expression data from neuroblastoma of TH-MYCN/KI Alk mice

Project description:Neuroblastoma is an embryonal neoplasm that remains of dramatic prognosis in its aggressive forms. Activating mutations of the ALK tyrosine kinase receptor have been identified in sporadic and familial cases of this cancer. We generated knock-in mice carrying the two most frequent Alk mutations observed in neuroblastoma patients. We used microarrays to detail the global programme of gene expression underlying the impact of ALK mutations on neuroblastoma formation in a MYCN amplified background. We selected several murine neuroblastoma tumors for RNA extraction and hybridization on Affymetrix microarrays. We generated three groups of tumors: 10 MYCN amplified tumors, 11 MYCN amplified/ALK F1174L tumors and 10 MYCN amplified/ALK R1275Q tumors.

2014-06-24 | E-GEOD-46583 | biostudies-arrayexpress

ATR inhibition enables complete tumour regression in ALK-driven NB mouse models

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.

2021-11-02 | PXD027187 | Pride

ALK signalling primes the DNA damage response sensitizing ALK-driven neuroblastoma to therapeutic ATR inhibition

Project description:High-risk neuroblastoma (NB) currently presents significant clinical challenges. MYCN and ALK, which are often involved in high-risk NB, lead to increased replication stress in cancer cells, providing options for therapeutic exploitation. We previously identified an ATR/ALK inhibitor combination as an effective therapeutic approach in two independent genetically modified mouse NB models. Here, we identify an underlying molecular mechanism, in which ALK signalling leads to phosphorylation of ATR and CHK1, supporting an effective DNA damage response. The importance of ALK inhibition is supported by mouse data, in which monotreatment with ATRi resulted in a robust initial response, but subsequent relapse, in contrast to a 14-day ALKi/ATRi combination treatment that resulted in robust and sustained responses. Finally, we show that the remarkable response to the 14-day combined ATR/ALK inhibition protocol reflects a robust differentiation response in the tumour, reprogramming tumour cells to a neuronal/Schwann cell lineage identity. Our results identify a unique ability of ATR inhibition to trigger neuroblastoma differentiation and underscore the importance of further exploring combined ALK/ATR inhibition in NB, particularly in high-risk patient groups with oncogene-induced replication stress.

2023-12-13 | PXD041824 | Pride

Transcriptional profiles of transgenic ALK^F1174L/MYCN vs. MYCN tumors

Project description:The ALK^F1174L mutation is associated with intrinsic and acquired resistance to crizotinib and cosegregates with MYCN in neuroblastoma. In this study, we generated a mouse model overexpressing ALK^F1174L in the neural crest. Comapred to mice expressing ALK^F1174L or MYCN alone, combined expression of the two aberrations led to development of neuroblastoma with a shorter latency and higher penetrance. Here, we evaluated the transcriptional profiles of MYCN-driven neuroblastomas with or without the expression of ALK^F1174L to determine the pathogenic consequences of the ALK^F1174L/MYCN interaction in neuroblastoma. 10 mice were analysed in this study. Five ALK^F1174L/MYCN tumors were compared with five MYCN tumors. Total RNA was extracted, samples were labeled and processed using the Agilent Low Input Quick Amp two color Cy3(sample) and Cy5 (mouse reference) labeling kit and hybridized to Agilent SurePrint G3 Mouse Gene Expression arrays.

2012-07-04 | E-GEOD-35560 | biostudies-arrayexpress

Expression data from neuroblastoma of TH-MYCN/KI Alk mice

2014-06-24 | GSE46583 | GEO

Transcriptional profiles of transgenic ALK^F1174L/MYCN vs. MYCN tumors

2012-07-05 | GSE35560 | GEO

Expression data from neuroblastoma of TH-MYCN/KI RetM919T mice

Project description:The RET gene has been identified previously as a target of activated ALK at the mRNA level in both human neuroblastoma cell lines and primary tumors as well as in murine tumors driven by mutated Alk and MYCN. Moreover, it has been shown that tumor growth of murine TH-MYCN/KI Alkmut tumors was impaired upon Ret inhibition by the vandetanib inhibitor, suggesting RET as a therapeutic target in ALK mutated neuroblastoma. To further demonstrate the crucial role of RET in ALK mutated driven neuroblastoma oncogenesis, transgenic TH-MYCN mice were bred with KI RetM919T tumors. We document an oncogenic cooperation between activated Ret and MYCN overexpression in neuroblastoma formation. We used microarrays to analyze the global programme of gene expression of MYCN/RetM919T tumors and compare these profiles with profiles of MYCN/Alkmut tumors (GSE46583). Altogether, our data show that MYCN/RetM919T tumors present with expression profiles close to MYCN/Alkmut tumors.

2017-09-15 | GSE72678 | GEO

Gene expression profiling of MYCN-driven neuroblastoma tumor development in the TH-MYCN mouse model.

Project description:Neuroblastoma is an embryonic tumor arising from immature sympathetic nervous system progenitor cells. MYCN and ALK are driver oncogenes both of which are specifically expressed during early neurogenesis. This is in line with the assumption that neuroblastoma arises through disruption of normal developmental processes. MYCN has a broad impact on the tumor phenotype; however, the details of the MYCN driven oncogenic program are far from clear. In order to gain further insight into the role of gene expression during neuroblastoma initiation and progression, we evaluated gene expression profiles of hyperplastic ganglia and tumors isolated from MYCN transgenic mice.

2016-02-28 | E-MTAB-3247 | biostudies-arrayexpress

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