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| Status |
Public on Jun 30, 2024 |
| Title |
Pre-clinical spheroid models identify BMX as a therapeutic target for metastatic MYCN non-amplified neuroblastoma (ChIP-Seq) |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
The development of targeted therapies has provided new hope for an increasing number of cancer patients affected by previously incurable diseases. The clinical success of this approach, however, is limited by numerous challenges, including a better control of cell plasticity, particularly in refractory and metastatic patients. Here we addressed this question in Neuroblastoma (NB), an aggressive pediatric malignancy, which remains a clinical challenge for high-risk patients. NB originates from neural crest-derived progenitors through defective differentiation programs combined with oncogenic activity due to genetic and epigenetic alterations. In order to identify critical genes responsible for tumor aggressiveness we performed combined chromatin and transcriptome analyses on matched primary xenografts, spheroids and differentiated adherent cultures, which we derived from metastatic non-MYCN amplified (nMNA) NB patients. Our approach identified the kinase BMX among the most differentially regulated genes between patient-derived xenografts and spheroids versus adherent models. We further found that BMX expression is associated with high tumor stage and poor patient survival in multiple NB transcriptomic datasets and critical to maintain the self-renewal and tumorigenic potential of NB spheroids. Moreover, we uncovered a positive correlation between BMX expression and the mesenchymal tumor cell phenotype, which was previously associated with increased chemo-resistance. Finally, we show that BMX inhibitors can readily reverse this cellular state, increase the sensitivity of NB spheroids toward standard of care chemotherapy, and reduce tumor growth in preclinical NB models. Altogether, our study identifies BMX as a novel promising therapeutic target for high-risk patients with relapsed or refractory nMNA NB tumors.
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| Overall design |
H3K4me3 ChIP-seq of matched neuroblastoma xenografts, spheroids and cells in adherent culture conditions
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Raw patient data is deposited on zenodo https://doi.org/10.5281/zenodo.7431535 due to privacy restrictions
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| Contributor(s) |
Sundaramoorthy S, Colombo D, Mühlethaler-Mottet A, Bardet AF, Riggi N |
| Citation(s) |
39133652 |
| |
| Submission date |
Jan 27, 2023 |
| Last update date |
Oct 08, 2024 |
| Contact name |
Anais Flore Bardet |
| Organization name |
IGBMC
|
| Street address |
1 rue Laurent Fries
|
| City |
Illkirch |
| ZIP/Postal code |
67404 |
| Country |
France |
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| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
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| Samples (12)
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| This SubSeries is part of SuperSeries: |
| GSE223902 |
Pre-clinical spheroid models identify BMX as a therapeutic target for metastatic MYCN non-amplified neuroblastoma |
|
| Relations |
| BioProject |
PRJNA928776 |
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