A Novel Oncogenic Function of PRC2 Heterogeneity in Medulloblastoma

Intratumor epigenetic heterogeneity is emerging as a key mechanism underlying tumor evolution and drug resistance. Medulloblastomas, the most common childhood malignant brain tumor, are classified into four subtypes including SHH medulloblastomas, which are characterized by elevated SHH signaling and a cerebellum granule neuron precursor (CGNP) cell-of-origin. Medulloblastomas are highly associated with epigenetic abnormalities. We observed that the histone H3K27 methyltransferase polycomb repressor complex 2 (PRC2) is often heterogeneous within individual SHH medulloblastoma tumors. Using mouse models, we showed that while a complete deletion of the PRC2 core subunit EED inhibited medulloblastoma growth, 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 EED deletion led to CGNP depletion and reduced occurrence of medulloblastoma. Surprisingly, we found that medulloblastomas with mosaic EED levels grew faster than did control wildtype tumors and expressed increased levels of oncogenes such as Igf2. Igf2 is directly repressed by PRC2 and has been demonstrated to be both necessary and sufficient for SHH medulloblastoma progression. We showed that IGF2 mediated the oncogenic effects of PRC2 heterogeneity in tumor growth. Using a human medulloblastoma cell line, we generated clones with different EED levels and confirmed that EEDlow cells could stimulate the growth of EEDhigh cells through derepressed IGF2 signals. Thus, PRC2 heterogeneity controls medulloblastoma growth through both intrinsic growth competence and non-cell autonomous mechanisms in distinct tumor subclones. We reveal a novel oncogenic function of PRC2 heterogeneity in tumor development.

Aberrant FGF signaling promotes granule neuron precursor expansion in SHH subgroup infantile medulloblastoma

Mutations in Sonic Hedgehog (SHH) signaling pathway genes, e.g. Suppressor of Fused (SUFU), drive granule neuron precursors (GNP) to form medulloblastomas (MBSHH). However, how different molecular lesions in the Shh pathway drive transformation is frequently unclear, and in particular, SUFU mutations in the cerebellum seem distinct. In this study, we show that fibroblast growth factor 5 (FGF5) signaling is integral for many infantile MBSHH cases. We found that FGF5 expression is uniquely upregulated in infantile MBSHH tumors. Also, in mice carrying loss-of-function SUFU mutations (Sufu-cKO), FGF5 is ectopically expressed specifically along the secondary fissure where GNPs harboring preneoplastic DNA lesions are massively expanded and FGFR signaling is also ectopically activated in this region. Treatment with an FGFR antagonist rescues the severe GNP hyperplasia and restores cerebellar architecture. Thus, direct inhibition of FGF signaling may be a promising and novel therapeutic candidate for infantile MBSHH.

Effects of Mating and Social Exposure on Cell Proliferation in the Adult Male Prairie Vole (Microtus ochrogaster)

Microtus ochrogaster is a rodent with a monogamous reproductive strategy characterized by strong pair bond formation after 6 h of mating. Here, we determine whether mating-induced pair bonding increases cell proliferation in the subventricular zone (SVZ), rostral migratory stream (RMS), and dentate gyrus (DG) of the hippocampus in male voles. Males were assigned to one of the four groups: (1) control: males were placed alone in a clean cage; (2) social exposure to a female (SE m/f): males that could see, hear, and smell a sexually receptive female but where physical contact was not possible, because the animals were separated by an acrylic screen with small holes; (3) social exposure to a male (SE m/m): same as group 2 but males were exposed to another male without physical contact; and (4) social cohabitation with mating (SCM): males that mated freely with a receptive female for 6 h. This procedure leads to pair bond formation. Groups 2 and 3 were controls for social interaction. Male prairie voles were injected with 5-bromo-2′-deoxyuridine (BrdU) during the behavioral tests and were sacrificed 48 h later. Brains were processed to identify the new cells (BrdU-positive) and neuron precursor cells (neuroblasts). Our principal findings are that in the dorsal region of the SVZ, SCM and SE m/f and m/m increase the percentage of neuron precursor cells. In the anterior region of the RMS, SE m/f decreases the percentage of neuron precursor cells, and in the medial region SE m/f and m/m decrease the number of new cells and neuron precursor cells. In the infrapyramidal blade of the subgranular zone of the DG, SE m/m and SCM increase the number of new neuron precursor cells and SE m/m increases the percentage of these neurons. Our data suggests that social interaction, as well as sexual stimulation, leads to pair bonding in male voles modulating cell proliferation and differentiation to neuronal precursor cells at the SVZ, RMS, and DG.