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

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Osteosarcoma (OS) is a common pediatric bone cancer.
• Amplification of chromosome 8q24, including the c-MYC oncogene, occurs in 20-30% of OS cases and is linked to poor prognosis.
• The role of c-MYC in modulating the tumor microenvironment (TME) in OS is not fully understood.

Purpose of the Study:

• To investigate the mechanisms by which c-MYC affects the OS tumor and its TME.
• To characterize a novel genetically engineered mouse model (GEMM) for studying c-MYC-driven OS.
• To identify molecular pathways regulated by c-MYC in OS.

Main Methods:

• Generation and molecular characterization of an osteoblast-specific c-MycT58A p53fl/+ knockin GEMM.
• Analysis of MYC-dependent gene expression signatures.
• Assessment of immune cell populations within the TME.
• In vitro and in vivo validation using cell lines and a degradation tag-MYC model system.

Main Results:

• The Myc-knockin GEMM exhibited rapid tumor development and high metastatic incidence.
• MYC-dependent gene signatures in the mouse model mirrored human hyperactivated MYC OS.
• Hyperactivated c-MYC led to an immune-depleted TME, characterized by reduced leukocytes, especially macrophages.
• c-MYC hyperactivation downregulated macrophage colony-stimulating factor 1 via increased microRNA 17/20a expression, reducing macrophage populations.

Conclusions:

• Hyperactivated c-MYC promotes aggressive OS phenotypes, including rapid growth and metastasis.
• c-MYC significantly impacts the OS immune landscape by creating an immune-depleted TME.
• A novel mechanism involving microRNA 17/20a and macrophage colony-stimulating factor 1 mediates c-MYC's effect on macrophage recruitment in OS.