PRC2 Heterogeneity Drives Tumor Growth in Medulloblastoma

Abstract

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 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 individual 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 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 wildtype 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. 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. Thus, PRC2 heterogeneity plays an oncogenic role in medulloblastoma through both intrinsic growth competence and non-cell autonomous mechanisms in distinct tumor subclones.

SETD2 loss in renal epithelial cells drives epithelial‐to‐mesenchymal transition in a TGF‐β‐independent manner

“…Examples of such paracrine interactions include glioblastoma, where cancer cells expressing mutant EGFR stimulate the growth of tumor cells with WT EGFR through cytokine secretion (IL‐6 and LIF) [ 49 ]. Moreover, in medulloblastoma, heterogeneous inactivation of the PRC2 complex results in a subpopulation of cells that are less fit, but secrete IGF2 that enhances overall tumor growth [ 50 ]. Given these examples, the paracrine signaling effects we observed where CM from SETD2 KO RPTEC stimulates migration and invasion of SETD2 WT cells may explain how SETD2 deficiency contributes to heterogeneity and promotes metastasis (despite SETD2‐deficient cells proliferating less rapidly).…”

Targeting H3K27me3 demethylase to inhibit Shh signaling and cholesterol metabolism in medulloblastoma growth

“…Epigenetic regulators play important roles in Shh signaling and medulloblastoma development ( 10 , 11 , 28 – 31 ). Previously we identified histone 3 lysine 27 trimethylation (H3K27me3) demethylase Jmjd3 as a key player in Shh target gene activation ( 10 ).…”