Role of repulsive guidance signaling and GPR180 in pediatric low-grade glioma infiltration
Pediatric low-grade gliomas (pLGGs) are the most common brain tumors in children with varying degrees of infiltration. Despite having a positive prognosis, if the standard treatment, gross total resection, is impossible due to tumor location or diffuseness, outcomes worsen. Development of targeted therapeutics for diverse subtypes of pLGGs is limited by a lack of genetic models. We generated five fly pLGG models using patient-derived fusion genes to investigate molecular subtype-specific pathology, and found glial overexpression of QKI::RAF1, associated with pilocytic astrocytomas and glioneuronal tumors, induced aberrant glial migration and infiltration. Both repulsive guidance signaling and GPR180/CG9304 mediated glial infiltration, which was suppressed by glial overexpression of Robo2 or PlexA/B, or knockdown of GPR180/CG9304. ROBO2 and GPR180/CG9304 were down and upregulated, respectively, in flies and patients with RAF fusions. Our study provides mechanistic insights into pLGG tumorigenesis and suggests targeting repulsive guidance signaling and GPR180/CG9304 as potential therapeutics for pLGG subtypes.
Authors
- Anahita Fathi Kazerooni (ORCID: https://orcid.org/0000-0001-7131-2261)
- Xin Chen (ORCID: https://orcid.org/0000-0001-7620-5975)
- Yuanquan Song (ORCID: https://orcid.org/0000-0001-7699-2059)
- Ariana Familiar (ORCID: https://orcid.org/0000-0002-9315-8653)
- Angela J. Waanders (ORCID: https://orcid.org/0000-0002-0571-2889)
- Geena Jung (ORCID: https://orcid.org/0000-0002-3228-4381)
- Payal Jain (ORCID: https://orcid.org/0000-0002-5914-9083)
- Zhi‐Chuan Sun
- Komal S. Rathi (ORCID: https://orcid.org/0000-0001-5534-6904)
- Joshua Straka
- Xi Huang (ORCID: https://orcid.org/0000-0002-7177-7525)
- Hannah M. Deutsch (ORCID: https://orcid.org/0000-0002-3757-6180)
- Mateusz Koptyra (ORCID: https://orcid.org/0000-0002-3857-6633)
- Adam Resnick (ORCID: https://orcid.org/0000-0003-0436-4189)
- Stephanie Sanchez-maldonado
- Feng Li (ORCID: https://orcid.org/0000-0003-4703-5537)
- Ali Nabavizadeh (ORCID: https://orcid.org/0000-0002-1611-5078)
- Zizhuo Liang
- Yuqi Sun (ORCID: https://orcid.org/0000-0002-7179-5045)
Institutions
- Children's Hospital of Philadelphia (US)
- Central South University (CN)
- Shanghai Jiao Tong University (CN)
- University of Toronto (CA)
- Fudan University (CN)
- Hospital for Sick Children (CA)
- Lurie Children's Hospital (US)
- SickKids Foundation (CA)
- Xiangya Hospital Central South University (CN)
- University of Pennsylvania (US)
Publication Details
- Journal
- npj Precision Oncology
- Published
- 2025-11-11
- DOI
- https://doi.org/10.1038/s41698-025-01121-2
- Citations
- 1
- Primary Topic
- Glioma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 1.63
Funders
- National Institutes of Health