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Integrated proteomics spotlight the proteasome as a therapeutic vulnerability in embryonal tumors with multilayered rosettes.
Dottermusch, Matthias; Biabani, Ali; Lempertz, Tasja; Schumann, Yannis; Navolic, Jelena; Godbole, Shweta; Obrecht, Denise; Frank, Stephan; Dorostkar, Mario M; Voß, Hannah; Schlüter, Hartmut; Rutkowski, Stefan; Schüller, Ulrich; Neumann, Julia E.
Afiliación
  • Dottermusch M; Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Biabani A; Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Lempertz T; Section of Mass Spectrometric Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Schumann Y; Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Navolic J; Chair for High Performance Computing, Helmut-Schmidt University, Hamburg, Germany.
  • Godbole S; Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Obrecht D; Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Frank S; Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Dorostkar MM; Division of Neuropathology, Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland.
  • Voß H; Center for Neuropathology and Prion Research, Ludwig Maximilian University, Munich, Germany.
  • Schlüter H; Section of Mass Spectrometric Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Rutkowski S; Section of Mass Spectrometric Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Schüller U; Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Neumann JE; Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Neuro Oncol ; 26(5): 935-949, 2024 May 03.
Article en En | MEDLINE | ID: mdl-38158710
ABSTRACT

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.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Neoplasias Encefálicas / Neoplasias de Células Germinales y Embrionarias / Proteómica / Complejo de la Endopetidasa Proteasomal Límite: Humans Idioma: En Revista: Neuro Oncol Asunto de la revista: NEOPLASIAS / NEUROLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Alemania

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Neoplasias Encefálicas / Neoplasias de Células Germinales y Embrionarias / Proteómica / Complejo de la Endopetidasa Proteasomal Límite: Humans Idioma: En Revista: Neuro Oncol Asunto de la revista: NEOPLASIAS / NEUROLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Alemania