Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Cell. 2014 Apr 24;157(3):580-94. doi: 10.1016/j.cell.2014.02.030. Epub 2014 Apr 10.
Developmental fate decisions are dictated by master transcription factors (TFs) that interact with cis-regulatory elements to direct transcriptional programs. Certain malignant tumors may also depend on cellular hierarchies reminiscent of normal development but superimposed on underlying genetic aberrations. In glioblastoma (GBM), a subset of stem-like tumor-propagating cells (TPCs) appears to drive tumor progression and underlie therapeutic resistance yet remain poorly understood. Here, we identify a core set of neurodevelopmental TFs (POU3F2, SOX2, SALL2, and OLIG2) essential for GBM propagation. These TFs coordinately bind and activate TPC-specific regulatory elements and are sufficient to fully reprogram differentiated GBM cells to "induced" TPCs, recapitulating the epigenetic landscape and phenotype of native TPCs. We reconstruct a network model that highlights critical interactions and identifies candidate therapeutic targets for eliminating TPCs. Our study establishes the epigenetic basis of a developmental hierarchy in GBM, provides detailed insight into underlying gene regulatory programs, and suggests attendant therapeutic strategies. PAPERCLIP:
发育命运的决定取决于主转录因子（TFs），它们与顺式调控元件相互作用，指导转录程序。某些恶性肿瘤可能也依赖于类似于正常发育的细胞层次结构，但叠加在潜在的遗传异常之上。在胶质母细胞瘤（GBM）中，一小部分干细胞样肿瘤增殖细胞（TPCs）似乎驱动肿瘤进展并导致治疗耐药，但仍知之甚少。在这里，我们确定了一组核心的神经发育 TF（POU3F2、SOX2、SALL2 和 OLIG2），它们对 GBM 的增殖是必不可少的。这些 TF 协调地结合并激活 TPC 特异性调节元件，足以将分化的 GBM 细胞完全重编程为“诱导”TPCs，重现了 TPCs 的表观遗传景观和表型。我们重建了一个网络模型，突出了关键的相互作用，并确定了消除 TPCs 的候选治疗靶点。我们的研究确立了 GBM 中发育层次的表观遗传基础，深入了解了潜在的基因调控程序，并提出了相应的治疗策略。
