Transglutaminase-2 promotes metastatic and stem-like phenotypes in osteosarcoma

Osteosarcoma (OS) is a highly aggressive mesenchymal malignancy and the most common primary bone tumor in the pediatric population. OS frequently presents with or develops distal metastases. Patients with metastatic disease have extremely poor survival rates, thus necessitating improved molecular insights into OS metastatic biology. Utilizing our previously characterized genetically engineered mouse model (GEMM) of metastatic OS, we identified enhanced differential expression of Transglutaminase-2 (TGM2) in metastatic OS. However, the role of TGM2 in sarcoma development and metastatic progression remains largely undefined. To further investigate the role of TGM2 in OS metastasis, we performed both gain-and loss-of-function studies for TGM2 in human and mouse OS cell lines. Our data provide evidence that enhanced expression of TGM2 in metastatic OS contributes to migratory and invasive phenotypes. Besides the effects on metastatic phenotypes, we also observed that TGM2 contributes to OS stem-like properties. In addition, treatment with transglutaminase inhibitors had analogous effects on proliferation and migration to TGM2 knockdown. Finally, in vivo xenograft studies demonstrated that TGM2 functionally alters metastatic potential and survival outcome. Together, these data highlight TGM2 as a pro-metastatic factor in OS and a potential avenue for future therapeutic intervention to inhibit metastatic disease.