| Title: |
DISRUPTING INTEGRIN SIGNALING IMPAIRS MIGRATION, MYC-DRIVEN PURINE BIOSYNTHESIS, AND STEMNESS IN H3K27M DIFFUSE MIDLINE GLIOMAS |
| Authors: |
Cartaxo, Rodrigo T.; de la Nava, Daniel; Nieblas‐Bedolla, Edwin; Niculcea, Michael; Ji, Sunjong; Natarajan, Siva Kumar; Adam, Tiffany; Clausen, Madison; Miclea, Madeline; Siada, Ruby; Schwark, Kallen; Gera, A; Doherty, Robert; Lyssiotis, Costas A.; Favro, Noemi; Covato, Carmelo; Brunschwig, Lucas S.; Waszak, Sebastian M.; Nuechterlein, Nicholas; Filbin, Mariella G.; Vo, Tuan; Dun, Matthew D.; Venneti, Sriram; Hara, Toshiro; Koschmann, Carl |
| Publication Year: |
2026 |
| Collection: |
Ecole Polytechnique Fédérale Lausanne (EPFL): Infoscience |
| Description: |
Diffuse midline glioma (DMG) is an aggressive pediatric brain tumor driven by the H3K27M histone mutation and represents the leading cause of cancer-related death in children. These tumors are highly infiltrative and can occasionally migrate to distant CNS regions. To uncover migration dependencies, we developed a novel two-step pooled whole-genome CRISPR-migration screen in metastatic H3K27M-DMG stem cells (n=3). Genes involved in focal adhesion (ITGB1 [integrin beta-1], CRKL, PARVA, PTK2, FERMT2) significantly restricted migration across all models; notably, only ITGB1 knockout (ITGB1-KO) completely abrogated migration. In H3K27M-DMG patient samples, unlike other brain tumor types, expression of ITGB1 correlates with higher glioma grade and worse survival. ITGB1-KO models demonstrated a reduction in expression of MYC target genes, including MYC-regulated metabolic genes involved in purine biosynthesis (e.g., IMPDH2). Further integrated RNA/metabolomic analyses revealed that loss of ITGB1 downregulates purine metabolism and the citric acid (TCA) cycle. Importantly, in in vivo models, ITGB1 deficiency significantly prolonged survival (UMPED83: 100 vs. 163.5 days, p=0.0003; pSCG-SVZ: 49 vs. 68 days, p=0.0095). Spatial transcriptomic and proteomic analyses of ITGB1-KO orthotopic H3K27M tumors showed widespread reduction in MYC target genes and depletion of precursor, undifferentiated (OPC-like), and an increase in differentiated (OC-like) K27M cells in the infiltrating edge. Direct pharmacological targeting of ITGB1 (anti-ITGB1 antibody, CNS delivered) significantly extended survival in DMG models (UMPED83: 100 vs. 125.5 days, p=0.0169; pSCG-SVZ: 49 vs. 72 days, p=0.0384). However, ITGB1-deficient pSCG-SVZ tumors exhibited compensatory alternative integrins upregulation (i.e., ITGB3, ITGB5). Promisingly, co-treatment with anti-ITGB1 antibody and cilengitide (ITGB3/5 inhibitor) further improved survival and resulted in 75% long-term survivors, free of disease. Strikingly, this combinatorial strategy failed to ... |
| Document Type: |
conference object |
| Language: |
English |
| ISSN: |
1522-8517; 1523-5866 |
| Relation: |
Neuro-Oncology; 7th Quadrennial Meeting of the World Federation of Neuro-Oncology Societies and 30th Society for Neuro-Oncology Annual Meeting & Education Day; https://infoscience.epfl.ch/handle/20.500.14299/258150 |
| DOI: |
10.1093/neuonc/noaf201.0084 |
| Availability: |
https://doi.org/10.1093/neuonc/noaf201.0084; https://infoscience.epfl.ch/handle/20.500.14299/258150; https://hdl.handle.net/20.500.14299/258150 |
| Accession Number: |
edsbas.2CB3C43A |
| Database: |
BASE |