Cancer and Stem Cell Epigenetics Section, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Building 37, Room 3140A, Bethesda, MD 20892, USA.
Cancer and Stem Cell Epigenetics Section, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Building 37, Room 3140A, Bethesda, MD 20892, USA; Department of Orthopaedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430070, China.
Stem Cell Reports. 2017 Jun 6;8(6):1630-1644. doi: 10.1016/j.stemcr.2017.04.029. Epub 2017 May 25.
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.
骨髓间充质干细胞（BMSCs）被认为是几种成骨肉瘤（OS）亚型的起源细胞。然而，指导 BMSCs 形成不同亚型 OS 的信号尚不清楚。在这里，我们发现自发转化的 p53 敲除（p53_KO）BMSCs 中默认的肿瘤类型是成骨细胞性 OS。由于 p53 缺失导致的这种默认肿瘤类型的发展可以被各种致癌信号所取代：RAS 将 p53_KO BMSCs 重编程为未分化肉瘤，AKT 增强成骨细胞性 OS，而 cFOS 促进软骨母细胞瘤 OS 的形成。我们专注于研究 cFOS 诱导的软骨母细胞瘤 OS 形成的机制。全基因组综合研究揭示了一种调控机制，即 cFOS 与关键软骨母细胞转录因子 Sox9 的启动子结合，并在 BMSCs 中诱导其转录。重要的是，SOX9 介导 cFOS 诱导的软骨母细胞瘤 OS 中的软骨形成。总之，癌基因决定了源自 BMSCs 的肿瘤类型，而 cFOS-SOX9 轴对于软骨母细胞瘤 OS 的形成至关重要。
