MYC Regulates CSF1 Expression via microRNA 17/20a To Modulate Tumor-Associated Macrophages in Osteosarcoma

Authors

Bikesh K Nirala
Tajhal D Patel
Lyazat Kurenbekova
Ryan Shuck
Atreyi Dasgupta
Nino Rainusso
Cristian Coarfa
Jason T Yustein

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

Published Open-Access

yes

Keywords

Humans, Mice, Animals, Tumor-Associated Macrophages, Macrophage Colony-Stimulating Factor, Osteosarcoma, Bone Neoplasms, MicroRNAs, Tumor Microenvironment, Oncology, Bone disease, Mouse models, Oncogenes

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.