Epigenetic Heterogeneity Drives Tumor Growth in Medulloblastoma
Introduction
Intratumor epigenetic heterogeneity is emerging as a key mechanism underlying tumor evolution and drug resistance. Epigenetic abnormalities frequently occur in medulloblastoma, the most common childhood malignant brain tumor. Medulloblastoma is classified into four subtypes including SHH medulloblastoma, which is characterized by elevated sonic hedgehog (SHH) signaling and a cerebellum granule neuron precursor (CGNP) cell-of-origin. Histone H3K27 methyltransferase polycomb repressor complex 2 (PRC2) is often heterogeneous within individual SHH medulloblastoma tumors. We study how PRC2 heterogeneity plays an oncogenic role in medulloblastoma through both intrinsic growth competence and non–cell autonomous mechanisms in distinct tumor subclones.
Methods
To determine the function of PRC2 in CGNPs and medulloblastomas, we deleted the PRC2 core subunit-encoding Eed gene specifically in CGNPs using a strong pan CGNP Atoh1-Cre driver or a weak TgAtoh1-Cre in a SHH medulloblastoma mouse model. We analyze the tumors using molecular, celluar, and genomic approaches. We further generated and studied PRC2 heterogeneity in a human medulloblastoma models. We analyzed PRC2 heterogeneity in human medulloblastoma samples and the association with tumor growth.
Results
In mouse models, complete deletion of the PRC2 core subunit EED inhibited medulloblastoma growth, while a mosaic deletion of EED significantly enhanced tumor growth. EED is intrinsically required for CGNP maintenance by inhibiting both neural differentiation and cell death. Complete deletion of EED led to CGNP depletion and reduced occurrence of medulloblastoma. Surprisingly, medulloblastomas with mosaic EED levels grew faster than control wild-type tumors and expressed increased levels of oncogenes such as Igf2, which is directly repressed by PRC2 and has been demonstrated to be both necessary and sufficient for SHH medulloblastoma progression. Insulin-like growth factor 2 (IGF2) mediated the oncogenic effects of PRC2 heterogeneity in tumor growth. Assessing clones of a human medulloblastoma cell line with different EED levels confirmed that EEDlow cells can stimulate the growth of EEDhigh cells through paracrine IGF2 signaling. We also confirm the presence of PRC2 heterogeneity in human medulloblastoma samples.
Conclusion
PRC2 heterogeneity is present in medulloblastoma and plays an oncogenic role in medulloblastoma through both intrinsic growth competence and non–cell autonomous mechanisms in distinct tumor subclones.