Aix Marseille University, CNRS, IBDM, Turing Centre for Living systems, Equipe Labellisée Ligue Contre le Cancer, Campus de Luminy Case 907, 13288 Cedex 09 Marseille, France.
Sci Adv. 2022 May 13;8(19):eabi4529. doi: 10.1126/sciadv.abi4529. Epub 2022 May 11.
COMPASS and Polycomb complexes are antagonistic chromatin complexes that are frequently inactivated in cancers, but how these events affect the cellular hierarchy, composition, and growth of tumors is unclear. These characteristics can be systematically investigated in neuroblast tumors in which cooption of temporal patterning induces a developmental hierarchy that confers cancer stem cell (CSC) properties to a subset of neuroblasts retaining an early larval temporal identity. Here, using single-cell transcriptomics, we reveal that the trithorax/MLL1/2-COMPASS-like complex guides the developmental trajectory at the top of the tumor hierarchy. Consequently, knockdown drives larval-to-embryonic temporal reversion and the marked expansion of CSCs that remain locked in a spectrum of early temporal states. Unexpectedly, this phenotype is amplified by concomitant inactivation of Polycomb repressive complex 2 genes, unleashing tumor growth. This study illustrates how inactivation of specific COMPASS and Polycomb complexes cooperates to impair tumor hierarchies, inducing CSC plasticity, heterogeneity, and expansion.
COMPASS 和 Polycomb 复合物是拮抗染色质复合物，在癌症中经常失活，但这些事件如何影响肿瘤的细胞层次结构、组成和生长尚不清楚。这些特征可以在神经母细胞瘤中进行系统研究，其中时间模式的选择会诱导出一种发育层次结构，赋予一小部分保留早期幼虫时间特征的神经母细胞癌症干细胞（CSC）特性。在这里，我们使用单细胞转录组学揭示了 trithorax/MLL1/2-COMPASS 样复合物在肿瘤层次结构的顶端指导发育轨迹。因此，下调会导致幼虫到胚胎的时间反转，并显著扩大 CSC，这些 CSC 仍然锁定在一系列早期时间状态中。出乎意料的是，这种表型会因同时失活 Polycomb 抑制复合物 2 基因而放大，从而引发肿瘤生长。这项研究说明了特定 COMPASS 和 Polycomb 复合物的失活如何合作损害肿瘤层次结构，诱导 CSC 可塑性、异质性和扩增。
