Journal Article

DKFZ-2024-01953

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Integration of Transcriptomics, Proteomics and Loss-of-function Screening Reveals WEE1 as a Target for Combination with Dasatinib against Proneural Glioblastoma.

Alhalabi, O. (First author)DKFZ* ; Göttmann, M. (First author)DKFZ* ; Gold, M. P. ; Schlue, S.DKFZ* ; Hielscher, T.DKFZ* ; Iskar, M.DKFZ* ; Kessler, T.DKFZ* ; Hai, L. ; Lokumcu, T.DKFZ* ; Cousins, C. C. ; Herold-Mende, C. ; Heßling, B.DKFZ* ; Horschitz, S. ; Jabali, A. ; Koch, P. ; Baumgartner, U. ; Day, B. W. ; Wick, W.DKFZ* ; Sahm, F.DKFZ* ; Krieg, S. M. ; Fraenkel, E. ; Phillips, E.DKFZ* ; Goidts, V. (Last author)DKFZ*

2024
Elsevier Science Amsterdam [u.a.]

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Please use a persistent id in citations: doi:10.1016/j.canlet.2024.217265

Abstract: Glioblastoma is characterized by a pronounced resistance to therapy with dismal prognosis. Transcriptomics classify glioblastoma into proneural (PN), mesenchymal (MES) and classical (CL) subtypes that show differential resistance to targeted therapies. The aim of this study was to provide a viable approach for identifying combination therapies in glioblastoma subtypes. Proteomics and phosphoproteomics were performed on dasatinib inhibited glioblastoma stem cells (GSCs) and complemented by an shRNA loss-of-function screen to identify genes whose knockdown sensitizes GSCs to dasatinib. Proteomics and screen data were computationally integrated with transcriptomic data using the SamNet 2.0 algorithm for network flow learning to reveal potential combination therapies in PN GSCs. In vitro viability assays and tumor spheroid models were used to verify the synergy of identified therapy. Further in vitro and TCGA RNA-Seq data analyses were utilized to provide a mechanistic explanation of these effects. Integration of data revealed the cell cycle protein WEE1 as a potential combination therapy target for PN GSCs. Validation experiments showed a robust synergistic effect through combination of dasatinib and the WEE1 inhibitor, MK-1775, in PN GSCs. Combined inhibition using dasatinib and MK-1775 propagated DNA damage in PN GCSs, with GCSs showing a differential subtype-driven pattern of expression of cell cycle genes in TCGA RNA-Seq data. The integration of proteomics, loss-of-function screens and transcriptomics confirmed WEE1 as a target for combination with dasatinib against PN GSCs. Utilizing this integrative approach could be of interest for studying resistance mechanisms and revealing combination therapy targets in further tumor entities.

Keyword(s): Loss-of-function shRNA screen ; Phosphoproteomics ; WEE1 ; computational integration ; dasatinib

Note: #EA:B067#LA:B067# / 2024 Sep 25:605:217265

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Contributing Institute(s):

1. B067 Juniorgruppe Brain Tumor Translational Target (B067)
2. C060 Biostatistik (C060)
3. B060 Molekulare Genetik (B060)
4. DKTK HD zentral (HD01)
5. KKE Neuroonkologie (B320)
6. Proteomics (W120)
7. KKE Neuropathologie (B300)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2024

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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