PRC2 Heterogeneity Drives Tumor Growth in Medulloblastoma

Intratumor epigenetic heterogeneity is emerging as a key mech-anism underlying tumor evolution and drug resistance. Epigenetic abnormalities frequently occur in medulloblastoma, the most com-mon childhood malignant brain tumor. Medulloblastoma is clas-sified 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. Here, we report that the histone H3K27 methyltransferase polycomb repressor complex 2 (PRC2) is often heterogeneous within indi-vidual SHH medulloblastoma tumors. 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 mainte-nance 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. Asses-sing 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. Thus, PRC2 heterogeneity plays an oncogenic role in medulloblastoma through both intrinsic growth competence and non-cell auton-omous mechanisms in distinct tumor subclones. Significance: The identification of an oncogenic function of PRC2 heterogeneity in medulloblastoma provides insights into subclone competition and cooperation during heterogeneous tumor evolution.

Automated summary

This study reveals that PRC2 heterogeneity plays an oncogenic role in SHH medulloblastoma, promoting tumor growth. Deletion of PRC2 core subunit EED inhibits tumor growth, while mosaic deletion of EED enhances tumor growth. The presence of EED is essential for maintaining cerebellum granule neuron precursors.