TMOD-04. BRAF V600E mutation induces TWIST1-mediated migration and leptomeningeal dissemination in glioblastoma
Year: 2025
Type: conference-abstract
Abstract: BRAF V600E mutations are found in 3–5% of glioblastoma (GBM) cases, and approximately half of these develop leptomeningeal dissemination (LMD), in contrast to only 4% in typical GBM. However, the mechanisms underlying the increased propensity for LMD in BRAF V600E-mutant GBM remain poorly understood. In this study, we utilized both human induced pluripotent stem cell (iPSC)-derived GBM models and patient-derived xenograft (PDX) models to investigate the molecular mechanisms of LMD. Compared to BRAF wild-type GBM iPSC models, the BRAF V600E-mutant models exhibited a distinctive perivascular invasion pattern. Furthermore, only the BRAF-mutant cells successfully established a spinal cord dissemination model following cisternal injection. Transcriptomic analysis revealed that the BRAF-mutant models showed downregulation of cell-cell adhesion gene signatures and upregulation of TWIST1 expression. Notably, knockout of TWIST1 abolished both the perivascular invasion pattern and spinal dissemination in the BRAF-mutant iPSC model. Similarly, TWIST1 knockout in the BRAF V600E-mutant GBM PDX model eliminated perivascular invasion and spinal cord dissemination. These findings suggest that the BRAF V600E mutation induces TWIST1 upregulation, thereby promoting migration and LMD. Our work highlights TWIST1 and its downstream pathways as potential therapeutic targets in BRAF V600E-mutant GBM with LMD.
Source: Neuro-Oncology
Authors: Yohei Miyake, Brett Taylor, Daisuke Kawauchi, Brandon Jones, Nidhi Nathwani, Raghavendra Valda, Donald Pizzo, Frank Furnari
Institution: University of California San Diego
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4416139773
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