MYC regulates CSF1 expression via microRNA 17/20a to modulate tumor-associated macrophages in osteosarcoma

• Type of Material: Article
• Authors: Bikesh K Nirala, Texas Children’s Cancer and Hematology Centers; Tajhal D Patel, Texas Children’s Cancer and Hematology Centers; Lyazat Kurenbekova, Texas Children’s Cancer and Hematology Centers; Ryan Shuck, Texas Children’s Cancer and Hematology Centers; Atreyi Dasgupta, Texas Children’s Cancer and Hematology Centers; Nino Rainusso, Texas Children’s Cancer and Hematology Centers; Cristian Coarfa, Baylor College of Medicine; Jason T Yustein, Emory University
• Language: English
• Date: 2023-07-10
• Publisher: American Society for Clinical Investigation
• Publication Version: Final Published Version
• Copyright Statement: © 2023 Nirala et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1172/jci.insight.164947
• Title of Journal or Parent Work: JCI insight
• Volume: 8
• Issue: 13
• Keywords: MicroRNAs; Mice; Mouse models; Tumor Microenvironment; Oncogenes; Macrophage Colony-Stimulating Factor; Osteosarcoma; Oncology; Humans; Bone Neoplasms; Bone disease; Animals; Tumor-Associated Macrophages
• Research Categories: Biology, Cell; Health Sciences, Oncology; Biology, Genetics; Biology, Molecular

Abstract

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.