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Functionally distinct ALK and ROS1 fusions detected in infant-type hemispheric gliomas converge on STAT3 and SHP2

Andreas Postlmayr1, Astrid Sanchez Bergman1, Jacob Torrejon Diaz2

  • 1Translational Brain Tumor Research, Division of Oncology and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.

Cell Reports
|March 6, 2026
PubMed

Insights

ALK and ROS1 fusions drive infant-type hemispheric gliomas (IHG). This study reveals fusion-specific functions and STAT3 activation, identifying SHP2 interactions with ROS1 fusions for potential pediatric glioma therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • ALK and ROS1 fusions are oncogenic drivers in infant-type hemispheric gliomas (IHG).
  • The heterogeneity of ALK and ROS1 fusion partners and their impact on glioma biology are not well understood.

Purpose of the Study:

  • To investigate the biological functions and oncogenic activities conferred by specific ALK and ROS1 fusion variants in IHG.
  • To identify common and fusion-specific molecular dependencies for therapeutic targeting.

Main Methods:

  • Integrative phospho-proteomic and transcriptomic analysis of five IHG-associated fusions (CCDC88A::ALK, PPP1CB::ALK, GOPC::ROS1, CLIP1::ROS1, KIF21A::ROS1).
  • Affinity purification mass spectrometry to identify protein-protein interactions.
  • Downstream pathway analysis.

Main Results:

  • Fusion-specific oncogenic functions were identified, including increased cell motility associated with microtubule-interacting fusions (CCDC88A::ALK, CLIP1::ROS1).
  • All studied fusions converge on STAT3 activation.
  • SHP2 directly interacts with ROS1 fusions but not ALK fusions; ALK fusions interact with SHC1/SHC3. ROS1 fusions lead to greater SHP2 phosphorylation, suggesting MAPK-independent functions.

Conclusions:

  • The 5' gene partner significantly influences the oncogenic functions of ALK and ROS1 fusions in IHG.
  • Convergent STAT3 activation and distinct SHP2/SHC interactions highlight fusion-specific dependencies.
  • These findings offer insights for developing targeted therapies for pediatric gliomas.
Keywords:
ALKCP: cancerROS1STAT3brain tumorscell motilitycell signalinggene fusionsinfant-type hemispheric gliomaspediatric gliomasreceptor tyrosine kinases

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