癌症研究
骨肉瘤
肿瘤微环境
下调和上调
生物
免疫系统
癌基因
小RNA
人口
巨噬细胞
体外
免疫学
细胞
基因
医学
遗传学
环境卫生
细胞周期
作者
Bikesh K. Nirala,Tajhal Patel,Lyazat Kurenbekova,Ryan L. Shuck,Atreyi Dasgupta,Nino Rainusso,Cristian Coarfa,Jason T. Yustein
出处
期刊:JCI insight
[American Society for Clinical Investigation]
日期:2023-07-10
卷期号:8 (13)
被引量:6
标识
DOI:10.1172/jci.insight.164947
摘要
Osteosarcoma (OS) is the most common primary bone tumor of childhood. Approximately 20%-30% of OSs carry amplification of chromosome 8q24, which harbors the oncogene c-MYC and correlates with a poor prognosis. To understand the mechanisms that underlie the ability of MYC to alter both the tumor and its surrounding tumor microenvironment (TME), we generated and molecularly characterized an osteoblast-specific Cre-Lox-Stop-Lox-c-MycT58A p53fl/+ knockin genetically engineered mouse model (GEMM). Phenotypically, the Myc-knockin GEMM had rapid tumor development with a high incidence of metastasis. MYC-dependent gene signatures in our murine model demonstrated significant homology to the human hyperactivated MYC OS. We established that hyperactivation of MYC led to an immune-depleted TME in OS demonstrated by the reduced number of leukocytes, particularly macrophages. MYC hyperactivation led to the downregulation of macrophage colony-stimulating factor 1, through increased microRNA 17/20a expression, causing a reduction of macrophage population in the TME of OS. Furthermore, we developed cell lines from the GEMM tumors, including a degradation tag-MYC model system, which validated our MYC-dependent findings both in vitro and in vivo. Our studies utilized innovative and clinically relevant models to identify a potentially novel molecular mechanism through which MYC regulates the profile and function of the OS immune landscape.
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