cFOS-SOX9 Axis Reprograms Bone Marrow-Derived Mesenchymal Stem Cells into Chondroblastic Osteosarcoma.
cFOS-SOX9 Axis Reprograms Bone Marrow-Derived Mesenchymal Stem Cells into Chondroblastic Osteosarcoma.
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DOI：
10.1016/j.stemcr.2017.04.029
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发表时间：
2017-06-06
影响因子：
5.9
通讯作者：
Huang J
中科院分区：
文献类型：
--
作者：
He Y;Zhu W;Shin MH;Gary J;Liu C;Dubois W;Hoover SB;Jiang S;Marrogi E;Mock B;Simpson RM;Huang J
骨髓间充质干细胞（BMSCs）被认为是骨肉瘤（OS）几种亚型的起源细胞。然而，指导骨髓间充质干细胞形成不同OS亚型的信号尚不清楚。在这里，我们发现自发转化p53敲除（p53_KO）骨髓间充质干细胞的默认肿瘤类型是成骨细胞骨肉瘤。这种由p53缺失引起的默认肿瘤类型的发展可以被各种致癌信号所覆盖：RAS将p53_KO BMSCs重编程为未分化肉瘤，AKT增强成骨细胞OS，而cFOS促进成软骨细胞OS的形成。我们重点研究cfos诱导成软骨细胞OS形成的机制。综合全基因组研究揭示了cFOS与关键成软骨细胞转录因子Sox9的启动子结合并诱导其在骨髓间充质干细胞中转录的调控机制。重要的是，SOX9介导cfos诱导成软骨性骨肉瘤的软骨形成。总之，癌基因决定了骨髓间充质干细胞衍生的肿瘤类型，而cFOS-SOX9轴对成软骨细胞OS的形成至关重要。p53_KO骨髓间充质干细胞的默认肿瘤类型是成骨肉瘤癌基因将p53_KO骨髓间充质干细胞重编程成不同的肉瘤cFOS促进p53_KO骨髓间充质干细胞成软骨肉瘤SOX9是cFOS促进成软骨肉瘤的介质在本文中，Huang及其同事发现p53敲除小鼠骨髓间充质干细胞产生的默认肿瘤类型是成骨肉瘤（osteoblastic osteosarcoma， OS），致癌信号可以覆盖这种默认的肿瘤类型选择。他们重点研究了cFOS驱动成软骨细胞OS的机制，并证明SOX9是cFOS的介质之一。
Bone marrow-derived mesenchymal stem cells (BMSCs) are proposed as the cells of origin of several subtypes of osteosarcoma (OS). However, signals that direct BMSCs to form different subtypes of OS are unclear. Here we show that the default tumor type from spontaneously transformed p53 knockout (p53_KO) BMSCs is osteoblastic OS. The development of this default tumor type caused by p53 loss can be overridden by various oncogenic signals: RAS reprograms p53_KO BMSCs into undifferentiated sarcoma, AKT enhances osteoblastic OS, while cFOS promotes chondroblastic OS formation. We focus on studying the mechanism of cFOS-induced chondroblastic OS formation. Integrated genome-wide studies reveal a regulatory mechanism whereby cFOS binds to the promoter of a key chondroblastic transcription factor, Sox9, and induces its transcription in BMSCs. Importantly, SOX9 mediates cFOS-induced cartilage formation in chondroblastic OS. In summary, oncogenes determine tumor types derived from BMSCs, and the cFOS-SOX9 axis is critical for chondroblastic OS formation. The default tumor type from p53_KO BMSCs is osteoblastic OS Oncogenes reprogram p53_KO BMSCs into different sarcomas cFOS promotes chondroblastic OS from p53_KO BMSCs SOX9 is a mediator of cFOS in promoting chondroblastic OS In this article, Huang and colleagues show that the default tumor type arising from p53 knockout mouse bone marrow-derived mesenchymal stem cells is osteoblastic osteosarcoma (OS), and oncogenic signals can override this default tumor type choice. They focus on studying the mechanisms underlying cFOS-driven chondroblastic OS and demonstrate that SOX9 is one of the mediators of cFOS.