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Integrated proteomics spotlight the proteasome as a therapeutic vulnerability in embryonal tumors with multilayered
Matthias Dottermusch1,2, Ali Biabani3, Tasja Lempertz1
1Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Background:
Embryonal tumors with multilayered rosettes (ETMR) are rare malignant embryonal brain tumors. The prognosis of ETMR is poor and novel therapeutic approaches are desperately needed. Comprehension of ETMR tumor biology is currently based on only few previous molecular studies, which mainly focused on the analyses of nucleic acids. In this study, we explored integrated ETMR proteomics.
Methods:
Using mass spectrometry, proteome data were acquired from 16 ETMR and the ETMR cell line BT183. Proteome data were integrated with case-matched global DNA methylation data, publicly available transcriptome data, and proteome data of further embryonal and pediatric brain tumors.
Results:
Proteome-based cluster analyses grouped ETMR samples according to histomorphology, separating neuropil-rich tumors with neuronal signatures from primitive tumors with signatures relating to stemness and chromosome organization. Integrated proteomics showcased that ETMR and BT183 cells harbor proteasome regulatory proteins in abundance, implicating their strong dependency on the proteasome machinery to safeguard proteostasis. Indeed, in vitro assays using BT183 highlighted that ETMR tumor cells are highly vulnerable toward treatment with the CNS penetrant proteasome inhibitor Marizomib.
Conclusions:
In summary, histomorphology stipulates the proteome signatures of ETMR, and proteasome regulatory proteins are pervasively abundant in these tumors. As validated in vitro, proteasome inhibition poses a promising therapeutic option in ETMR.
Insights
Embryonal tumors with multilayered rosettes (ETMR) are rare brain tumors with poor prognosis. Proteomic analysis reveals ETMR cells depend on proteasome machinery, making proteasome inhibition a promising therapeutic strategy.
Area of Science:
- Neuro-oncology
- Proteomics
- Cancer Biology
Background:
- Embryonal tumors with multilayered rosettes (ETMR) are rare, aggressive pediatric brain tumors.
- Current understanding of ETMR biology is limited, with few molecular studies focusing on nucleic acids.
- Novel therapeutic strategies are urgently needed due to the poor prognosis of ETMR.
Purpose of the Study:
- To investigate the proteome of ETMR to uncover novel therapeutic targets.
- To integrate proteomic data with other molecular data for a comprehensive understanding of ETMR.
- To explore the therapeutic potential of proteasome inhibition in ETMR.
Main Methods:
- Mass spectrometry was used to acquire proteome data from 16 ETMR samples and the BT183 cell line.
- Proteome data were integrated with DNA methylation, transcriptome, and other embryonal/pediatric brain tumor proteome data.
- In vitro assays were performed using the BT183 cell line to test the efficacy of proteasome inhibition.
Main Results:
- Proteome-based clustering correlated ETMR histomorphology with distinct molecular signatures (neuronal vs. stemness/chromosome organization).
- ETMR and BT183 cells showed abundant proteasome regulatory proteins, indicating a reliance on proteasome machinery for proteostasis.
- In vitro studies demonstrated high vulnerability of ETMR tumor cells to the proteasome inhibitor Marizomib.
Conclusions:
- ETMR histomorphology is reflected in its proteome signatures.
- Abundant proteasome regulatory proteins in ETMR suggest a dependency on this pathway.
- Proteasome inhibition represents a promising therapeutic avenue for ETMR, as validated in vitro.
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