Comparative responses to demethylating therapy in animal models of osteosarcoma

TL;DR

Decitabine treatment inhibits tumor growth and metastasis in human and canine osteosarcoma by restoring estrogen receptor signaling and promoting bone cell differentiation.

Contribution

Demonstrates the effectiveness of demethylating therapy in canine osteosarcoma models, extending findings from human studies.

Findings

DAC treatment increased ALPL expression and enhanced differentiation in OSA cell lines.

DAC suppressed tumor growth and metastasis in both human and canine OSA models.

DAC altered immune response and cell cycle pathways, with greater effects in models with higher DNMT expression.

Abstract

The demethylating agent decitabine (DAC) effectively inhibits tumor growth and metastasis by targeting ESR1 methylation to restore estrogen receptor alpha (ERα) signaling and promoting cellular differentiation in models of human osteosarcoma (OSA). Whether this pathway can be targeted in canine OSA patients is unknown.

Canine OSA tumor samples were tested for ERα expression and ESR1 promoter methylation. Human (MG63.3) and canine (MC-KOS) OSA cell lines and murine xenografts were treated with DAC in vitro and in vivo, respectively. Samples were assessed using mRNA sequencing and tissue immunohistochemistry.

ESR1 is methylated in a subset of canine OSA patient samples and the MC-KOS cell line. DAC treatment led to enhanced differentiation as demonstrated by increased ALPL expression, and suppressed tumor growth in vitro and in vivo. Metastatic progression was inhibited, particularly in the MG63.3 model, which expresses higher levels of DNA methyltransferases DNMT1 and 3B. DAC treatment induced significant alterations in immune response and cell cycle pathways.

DAC treatment activates ERα signaling, promotes bone differentiation, and inhibits tumor growth and metastasis in human and canine OSA. Additional DAC-altered pathways and species- or individual-specific differences in DNMT expression may also play a role in DAC treatment of OSA.

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