Epigenetic plasticity as a novel target for cancer treatment

胶质母细胞瘤是最常见和致命的原发性脑肿瘤，其特点是肿瘤内和肿瘤间的异质性，组织学上的细胞类型不同。肿瘤内这种不同的癌细胞亚群与手术和化疗后存活的细胞存在联系，形成复发性病变，对进一步治疗有抵抗力。阐明胶质母细胞瘤组织异质性的分子机制是开发有效治疗这种可怕疾病的基本要求。我们发现EZH2/PRC2介导的控制肿瘤细胞可塑性的H3K27me3可能提供了一个限制肿瘤功能异质性的靶点，鉴于这种异质性所赋予的巨大耐药机制，这是对所有以癌细胞为中心的药物的核心挑战。为了鉴定EZH2/PRC2抑制剂，我们开发了一种高通量筛选化学物质，并分析了15,000种化合物。

Glioblastoma is the most common and deadly primary brain tumor, which is characterized by intratumoral and intertumoral heterogeneity with histologically different types of cells. Such multiple distinct subpopulations of cancer cells within tumors link to the existence of cells that survive surgery and chemotherapy to form recurrent lesions that are resistant to further treatments. Elucidating the molecular mechanisms underlying tissue heterogeneity of glioblastoma is a fundamental requirement for the development of effective treatments for this dreadful disease. We revealed that H3K27me3 mediated by EZH2/PRC2, which controls tumor cell plasticity, may provide a target to restrict the functional heterogeneity in tumors, a core challenge to all cancer cell-centric drugs given the huge reservoir of resistance mechanisms which such heterogeneity confers. In order to identify the EZH2/PRC2 inhibitor, we developed a high-throughput screening for chemicals and assayed 15,000 compounds.