cFOS-SOX9 Axis Reprograms Bone Marrow-Derived Mesenchymal Stem Cells into Chondroblastic Osteosarcoma

Stem Cell Reports

Wendy Dubois¹  Joy Gary²  Beverly Mock²  Wentao Zhu³  Jing Huang³  Yunlong He³  Min Hwa Shin³  Eryney Marrogi³  Shunlin Jiang³  Shelley B. Hoover⁴  R. Mark Simpson⁴  Chengyu Liu⁵ 

[1] Animal Models Core Facility, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA;Cancer Genetics Section, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, 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;Molecular Pathology Unit, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA;Transgenic Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA;

关键词: mesenchymal stem cells;    p53;    osteosarcoma;    cFOS;    SOX9;    RAS;    AKT;    stem cells;    cancer;    cancer stem cells;   

DOI  :  10.1016/j.stemcr.2017.04.029

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown