PXA study

Pleomorphic xanthoastrocytomas (PXAs) are rare glial tumors of adolescents and young adults that commonly harbor BRAFV600E mutations with concurrent CDKN2A/B loss. Despite multi-modal therapies, survival remains poor. We assembled one of the largest PXA cohorts to date with long-term follow-up, including matched primary and relapse samples, to investigate malignant evolution and the tumor microenvironment. Multi-omic analyses integrating bulk and single-cell profiling, spatial transcriptomics, and proteomics provided a comprehensive view of PXA biology and immune dynamics across recurrences. The genomic landscape was largely stable, with variable mutational burden unrelated to outcome. Transcriptional profiling revealed two major tumor populations: an immature, SOX9+ astrocytic population associated with sparse microglia, and a fibroblast-like population enriched in immune cells, dominated by exhausted T cells and immunosuppressive macrophages, yet notably depleted of microglia. These are unique features among brain tumors. Immune enrichment in fibroblast-like regions correlated with CXCL12 expression and recruitment of CXCR4⁺ immune cells, whereas SOX9-positive astrocytic regions expressed CXCL14, an inhibitor of the CXCL12–CXCR4 axis, driving immune exclusion. Longitudinal analyses showed that dominance of SOX9+ astrocyte-like cells and loss of T cells predicted aggressive, fatal progression. Our data suggest that PXAs arise from CXCL12-expressing meningeal fibroblasts, where oncogenic BRAF signaling, facilitated by concurrent CDKN2A/B loss, induces SOX2, SOX9, and NFIB expression, reprogramming these cells into highly invasive, CXCL14-expressing, immature astrocytes, which drive immune depletion and poor outcome. Together, these findings define the cellular and immune context of PXA, identify prognostic biomarkers, and uncover therapeutic vulnerabilities.

• Type: Metagenomics
• Archive: European Genome-phenome Archive (EGA)