Hendrikse, L. | Search bioRxiv

bioRxiv2026

Medulloblastoma Forms Symbiotic Metabolic Partnerships with Macrophages to Establish Leptomeningeal Metastases

Leptomeningeal metastases are the primary source of morbidity and mortality for pediatric medulloblastoma patients. Due to limited surgical sampling of metastases in patients, little is understood of the mechanisms of metastasis. Here, we identify biologically distinct quiescent small metastases (designated as micrometastases) and mitotically active larger metastases (macrometastases). Macrometastases are more metabolically active than micrometastases and contain higher levels of lipids, particularly cholesterol. Macrometastases secrete CXCL12, which attracts lipid-laden macrophages into the tumor. Lipid-laden macrophages upregulate the cholesterol transporter ABCG1, promoting the efflux of free cholesterol, which is then taken up by tumor cells via the HDL receptor SCARB1. CXCL12-driven macrophage recruitment and exogenous cholesterol are sufficient and necessary to drive progression of medulloblastoma leptomeningeal metastases in vivo. High fat diets drive metastatic progression in vivo. Dietary or pharmacological interventions targeting the CXCL12-SCARB1-cholesterol axis represent therapeutic strategies to either prevent or treat medulloblastoma leptomeningeal metastases.

cancer biology↗

bioRxiv2025

Human stem cell models for group 3 medulloblastoma uncover JARID1B as a regulator of the chromatin landscape.

Medulloblastoma (MB) is one of the most prevalent malignant brain tumors in children, with tremendous cognitive and neuroendocrine disability among survivors. Group 3 MB (G3MB) has poor overall survival at <50%, high frequencies of metastases, and no targeted therapies. Amplification of MYC and activation of TGF{beta} signaling occur frequently in G3MB. Many tumors have no reported mutations, suggesting epigenetic drivers. We here describe novel humanized models for G3MB from human induced pluripotent stem cells (hiPSC). By transducing hiPSC-derived neuroepithelial stem cells (NESC), we determined that: 1) both MYC and TGF{beta} effectors drove tumors in vivo; 2) MYC/TGF{beta}R1 in combination led to more aggressive tumors and resistance to clinical inhibitors of TGF{beta}, and 3) NESC-derived tumors clustered with human G3MB. To decipher mechanisms, we integrated RNA-sequencing with CUT&RUN (for MYC genomic localization and post-translational modification of histones). MYC-bound neural developmental genes were repressed in MYC/TGF{beta}R1 co-driven lines. Gene signatures associated with the Polycomb Repressive Complex (PRC) demarcated with H3K27me3; the histone mark directly regulated by PRC. We identified JARID1B, a MYC binding partner and H3K4me3 demethylase, as a regulator of repressed neural genes. Primary G3MB also showed increased levels of H3K27me3 concurrent with higher expression of JARID1B. Knockdown of JARID1B in human G3MB cell lines reduced growth, supporting potential as a therapeutic target. We conclude that a MYC-TGF{beta}-JARID1B axis represses target genes to drive G3MB and present new humanized models for G3MB to understand epigenetic dysregulation in G3MB.

cancer biology↗