Journal Article

DKFZ-2026-00539

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Functionally distinct ALK and ROS1 fusions detected in infant-type hemispheric gliomas converge on STAT3 and SHP2 activation.

Postlmayr, A. ; Sanchez Bergman, A. ; Torrejon Diaz, J. ; Ciraulo, B. ; Yan, S. ; Hofmann, N.DKFZ* ; Carbajal, S. ; Dobler, R. ; Machaalani, C. ; Schönholzer, M. T. ; Priego Gonzalez, L. ; De Micheli, A. J. ; Berenjeno-Correa, E. ; Baroncini, L. ; Grotzer, M. A. ; Tabori, U. ; Hawkins, C. ; Ayrault, O. ; Zuckermann, M.DKFZ* ; Baumgartner, M. ; Guerreiro Stücklin, A. S.

2026
Cell Press Maryland Heights, MO

Abstract: ALK and ROS1 fusions are key drivers of infant-type hemispheric gliomas (IHG). With diverse gene partners, the impact of ALK and ROS1 oncoprotein heterogeneity on glioma biology remains unknown. We developed an integrative phospho-proteomic and transcriptomic approach to discover biological functions regulated by five IHG-associated fusions: CCDC88A::ALK, PPP1CB::ALK, GOPC::ROS1, CLIP1::ROS1, and KIF21A::ROS1. Here, we report fusion-specific oncogenic functions conferred by the 5' gene partner, including increased cell motility driven by microtubule-interacting fusions CCDC88A::ALK and CLIP1::ROS1. All studied fusions converge on STAT3 activation. Using affinity purification mass spectrometry, we identified SHP2 in direct interaction with all three ROS1 oncoproteins but with none of the ALK oncoproteins, which in turn interact with SHC1/SHC3. ROS1 fusions phosphorylate SHP2 to a greater extent than ALK fusions, and analyses of downstream pathways suggest MAPK-independent, non-canonical SHP2-driven functions. Our findings reveal both common and fusion-specific dependencies, offering opportunities to optimize therapeutic strategies for pediatric gliomas.

Keyword(s): ALK ; CP: cancer ; ROS1 ; STAT3 ; brain tumors ; cell motility ; cell signaling ; gene fusions ; infant-type hemispheric gliomas ; pediatric gliomas ; receptor tyrosine kinases

Note: #NCTZFB26#

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Contributing Institute(s):

1. B062 Pädiatrische Neuroonkologie (B062)
2. Koordinierungsstelle NCT Heidelberg (HD02)

Research Program(s):

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

Appears in the scientific report 2026

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Database coverage:
; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; DOAJ Seal ; Essential Science Indicators ; Fees ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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