Epigenomic characterization of paired primary and metastatic osteosarcoma tumors to define novel therapeutic targets
Distant metastases cause more than 90% of cancer-related mortality. Children suffering from osteosarcoma, where the typical route of spread is from bone to lung, are no exception. Unfortunately, 40% of these pediatric patients fail to be cured by the current standard of care and ultimately succumb to metastatic disease. Recent clinical trials have demonstrated that intensification of chemotherapy regimens does not provide added benefit and outcomes for patients have not significantly improved for over 25 years. There is therefore a pressing clinical need to determine the factors responsible for lung metastasis in osteosarcoma to facilitate development of novel anti-metastatic therapies and prognostic biomarkers. Gene enhancer elements are known to be the key determinants of cell state changes and to mediate responses to exogenous stimuli. My lab and others have previously shown that aberrant enhancer activity is an essential driver of tumor formation and maintenance. Based on these fundamental principles, we recently investigated the role of enhancer dysregulation in pre-clinical models of osteosarcoma metastasis. We completed epigenomic enhancer analysis in isogenic pairs of non-metastatic and highly lung metastatic osteosarcoma cell lines. Compared to non-metastatic progenitors, the metastatic cells show differences in enhancer usage at hundreds of loci across the epigenome. These enhancer differences are highly predictive of altered gene expression as cells complete the steps of metastasis. Furthermore, blocking the activation of these genes markedly impedes metastatic progression and prolongs survival in pre-clinical mouse models. As such, these aberrant enhancer elements and the genes that they regulate represent a ripe crop of candidate anti-metastatic therapeutic targets. We now propose epigenomic enhancer profiling of a cohort of matched primary and metastatic human osteosarcoma tumor pairs. This cohort of specimens, all with corresponding clinical information, is an incredibly valuable resource that when combined with our enhancer-mapping and functional strategies, provides an unprecedented opportunity to pinpoint genes that drive metastasis in osteosarcoma and could reveal commonalities among metastatic cells exploitable as therapeutic targets and prognostic biomarkers in human osteosarcoma patients.