Epigenetic plasticity as a novel target for cancer treatment

胶质母细胞瘤是最常见和最致命的原发脑肿瘤，其特点是瘤内和瘤间具有不同类型的细胞。肿瘤内这种多个不同的癌细胞亚群与手术和化疗后存活的细胞的存在有关，这些细胞形成了对进一步治疗具有抵抗力的复发病变。阐明胶质母细胞瘤组织异质性的分子机制是开发这种可怕疾病的有效治疗方法的基本要求。我们发现，由EZH2/PRC2介导的H3K27me3控制肿瘤细胞的可塑性，可能提供一个靶点来限制肿瘤功能的异质性，这是对所有以癌细胞为中心的药物的核心挑战，因为这种异质性提供了巨大的耐药机制。为了鉴定EZH2/PRC2抑制剂，我们开发了一种高通量的化学物质筛选方法，并检测了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.