Language
English
Publication Date
7-10-2023
Journal
JCI Insight
DOI
10.1172/jci.insight.164947
PMID
37279073
PMCID
PMC10371352
PubMedCentral® Posted Date
7-10-2023
PubMedCentral® Full Text Version
Post-print
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.
Keywords
Humans, Mice, Animals, Tumor-Associated Macrophages, Macrophage Colony-Stimulating Factor, Osteosarcoma, Bone Neoplasms, MicroRNAs, Tumor Microenvironment, Oncology, Bone disease, Mouse models, Oncogenes
Published Open-Access
yes
Recommended Citation
Nirala, Bikesh K; Patel, Tajhal D; Kurenbekova, Lyazat; et al., "MYC Regulates CSF1 Expression via microRNA 17/20a To Modulate Tumor-Associated Macrophages in Osteosarcoma" (2023). Faculty and Staff Publications. 1929.
https://digitalcommons.library.tmc.edu/baylor_docs/1929
Included in
Biological Phenomena, Cell Phenomena, and Immunity Commons, Life Sciences Commons, Medical Cell Biology Commons, Medical Microbiology Commons, Medical Molecular Biology Commons, Musculoskeletal Diseases Commons, Oncology Commons