Metastatic OsteosMetasarcoma Escapes from Oncogene Addiction

Osteosarcoma (OS) is the most frequent primary malignant bone tumor in urgent need of better therapies. The 5-year overall survival for OS patients with metastasis, the spread of cancer cells from the place where they first formed to another part of the body, and/or relapse, any form of cancer that has returned or recurred when a fraction of primary tumor cells evade the effects of treatment and survive in small spaces that are undetectable by diagnostic tests, is ~20%. Recurrent OS occurs in 30 - 40% of patients with primary tumor and lung metastases can be detected at diagnosis in 15 - 20% of patients, while the majority of OS patients could have very small metastasis, which is below the detection limit. The current diagnosis of OS is based on clinical, radiographical and histological assessments and no reliable prognostic biomarker is available. Although histological evaluation provides diagnostic value, the abovementioned conventional approaches are limited to find characteristics of metastatic OS, a main obstacle for effective therapy and mechanisms of recurrence and metastasis, and how both processes are mechanistically linked to each other have not been thoroughly investigated. To address this question, we developed a new model system that resembles human OS in which tumors exhibit metastasis and relapse. The main objective of this study is to characterize OS between different tumor growth stages and discover key mechanistic events involved in recurrence and metastasis. Integrative analyses of this study will enable matching analysis of primary tumors, recurrent tumors and metastases and shed light on the developmental processes of OS. This will be accomplished by combining several cutting-edge technologies, such as an experimental OS model, mapping/measuring gene activity, characterizing cellular features and computational analysis. Identification of biological events associated with OS metastasis and recurrence would be a great innovation to enable proper disease management and reduction of the burden of disease. This study will identify underlying mechanisms regulating metastasis and recurrence of OS and reveal the relationship between these processes and the malignancy of the disease, providing important information for therapeutically actionable targets to augment current OS therapies.