The Role of Exosomal DNA as an Activator of the Anti-tumor Immune Response in Metastatic Pediatric Osteosarcoma
Mentor: Dr. David Lyden
Osteosarcoma is the most common bone tumor in children and has poor prognosis for patients presenting with metastasis. To better treat these patients, it is vital that we investigate the biological mechanisms causing osteosarcoma metastasis. It is currently understood that tumor cells secrete factors that allow for communication with other cells at distant sites. These tumor-secreted factors include exosomes (small nano-sized vesicles that transport DNA, RNA and proteins). This communication primes distant sites for pre-metastatic niche formation and subsequent metastatic invasion. Research in Dr. Lyden’s laboratory demonstrates that exosome DNA (exoDNA) from primary tumor cells is inversely correlated with tumor metastatic potential. Moreover, he has identified genes that are directly involved in exoDNA packaging, allowing for manipulation of the amount of DNA packaged in exosomes. I hypothesize that exosomes with high exoDNA content stimulate anti-tumor immune responses, impairing tumor progression and resulting in reduced metastasis in osteosarcoma. In this study, I will use osteosarcoma cell lines, in which exoDNA levels are genetically manipulated, to determine whether exoDNA high exosomes or exoDNA low exosomes interact with immune cells as well as cells at distant organ sites. Additionally, I will isolate exosomes and subsequently exoDNA from the plasma of pediatric osteosarcoma patients both with and without metastasis and age-matched healthy control subjects to determine whether low plasma exoDNA could be used as a biomarker to predict metastatic risk.
