RNA-seq Profiles in Preferential Iron Trafficking Characterizes Glioblastoma Stem-like Cells. Homo sapiens

Glioblastomas display hierarchies with self-renewing cancer stem-like cells (CSCs). RNA sequencing and enhancer mapping revealed regulatory programs unique to CSCs causing upregulation of the iron transporter transferrin, the top differentially expressed gene compared to tissue-specific progenitors. Direct interrogation of iron uptake demonstrated CSCs potently extract iron from the microenvironment more effectively than other tumor cells. Systematic interrogation of iron flux determined that CSCs preferentially require transferrin receptor and ferritin - two core iron regulators - to propagate and form tumors in vivo. Depleting ferritin disrupted CSC mitotic progression, through the STAT3-FoxM1 regulatory axis, revealing an iron-regulated CSC pathway. Iron is a unique, primordial metal fundamental for earliest life forms, and on which CSCs have an epigenetically programmed, targetable dependence. Overall design: RNA-seq of primary patient-derived GBM cancer stem cells and normal human neural progenitor cells

胶质母细胞瘤（Glioblastomas）呈现出包含自我更新型癌干细胞样细胞（cancer stem-like cells, CSCs）的层级结构。通过RNA测序（RNA sequencing）与增强子图谱绘制（enhancer mapping），研究人员鉴定出癌干细胞样细胞特有的调控程序，该程序可介导铁转运蛋白转铁蛋白（transferrin）的上调；相较于组织特异性祖细胞，该蛋白为差异表达最为显著的基因。直接检测铁摄取情况的实验证实，癌干细胞样细胞从肿瘤微环境中摄取铁的能力显著强于其他肿瘤细胞。对铁通量的系统性分析表明，癌干细胞样细胞的增殖与体内成瘤过程优先依赖于转铁蛋白受体（transferrin receptor）与铁蛋白（ferritin）这两种核心铁调控因子。通过敲除铁蛋白，可经STAT3-FoxM1调控轴破坏癌干细胞样细胞的有丝分裂进程，由此揭示了一条铁调控的癌干细胞样细胞通路。铁是一种独特的原始金属，是早期生命形式的基础，而癌干细胞样细胞对其存在表观遗传编程的、可靶向的依赖性。整体实验设计：对患者原代分离的胶质母细胞瘤癌干细胞样细胞与正常人类神经祖细胞进行RNA测序（RNA-seq）。