Tumor cells are often heterogeneous and contain subclones with genetic and epigenetic variations. One frontier of cancer study is how cancer subclones compete and cooperate during cancer development. Medulloblastomas (MB), the most common childhood malignant brain tumor, are highly heterogeneous between different tumors and within a single tumor, which complicates treatment options. Sonic hedgehog (SHH) type MBs compose 25% of all MBs and are characterized by elevated SHH signaling and a cerebellum granule neuron precursor (CGNP) cell-of-origin. One important characteristic of MB is its significant association with epigenetic abnormalities, including those in the H3K27me3 methyltransferase P...
Read More
Tumor cells are often heterogeneous and contain subclones with genetic and epigenetic variations. One frontier of cancer study is how cancer subclones compete and cooperate during cancer development. Medulloblastomas (MB), the most common childhood malignant brain tumor, are highly heterogeneous between different tumors and within a single tumor, which complicates treatment options. Sonic hedgehog (SHH) type MBs compose 25% of all MBs and are characterized by elevated SHH signaling and a cerebellum granule neuron precursor (CGNP) cell-of-origin. One important characteristic of MB is its significant association with epigenetic abnormalities, including those in the H3K27me3 methyltransferase Polycomb repressor complex 2 (PRC2). In human SHH MBs, PRC2 have been shown to have both oncogenic and tumor suppressor functions in different contexts. Although no mutations of PRC2 subunits were identified, PRC2 levels are often heterogeneous in a single tumor. However, it remains unknown whether PRC2 heterogeneity plays any role in tumor development. The goal of this study is to determine how PRC2 controls MB growth through both intrinsic growth competence and non-cell autonomous mechanisms. Using mouse models of SHH MB and a MB cancer cell line, we observed that while a complete deletion of the PRC2 core subunit EED inhibited MB growth, a mosaic deletion of EED significantly enhanced tumor growth. We identified secreted oncogenic factors such as IGF2 as potential PRC2 targets that promote overall tumor growth. Thus, we hypothesize that in a heterogeneous MB tumor that contains both PRC2-high and PRC2-low cells, the PRC2-low subclones, despite having a lower growth competence, enhance PRC2-high subclone and overall tumor growth, which is likely mediated by derepressed IGF2 and the activated PI3K/AKT pathway. In this proposal, we will gain a comprehensive understanding of the significance of PRC2 heterogeneity in MB and test potential new MB treatment targets.
Read Less
