Integrated proteomics spotlight the proteasome as a therapeutic vulnerability in Embryonal Tumors with Multilayered Rosettes

TY - JOUR

T1 - Integrated proteomics spotlight the proteasome as a therapeutic vulnerability in Embryonal Tumors with Multilayered Rosettes

AU - Dottermusch, Matthias

AU - Biabani, Ali

AU - Lempertz, Tasja

AU - Schumann, Yannis

AU - Navolic, Jelena

AU - Godbole, Shweta

AU - Obrecht, Denise

AU - Frank, Stephan

AU - Dorostkar, Mario M

AU - Voß, Hannah

AU - Schlüter, Hartmut

AU - Rutkowski, Stefan

AU - Schüller, Ulrich

AU - Neumann, Julia E

N1 - © The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.

PY - 2024/5/3

Y1 - 2024/5/3

N2 - 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.

AB - 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.

U2 - 10.1093/neuonc/noad265

DO - 10.1093/neuonc/noad265

M3 - SCORING: Journal article

C2 - 38158710

VL - 26

SP - 935

EP - 949

JO - NEURO-ONCOLOGY

JF - NEURO-ONCOLOGY

SN - 1522-8517

IS - 5

ER -