Epigenetic drivers of lung metastasis in osteosarcoma

PROJECT SUMMARY Osteosarcoma (OS) metastasis is the leading driver of mortality, but there are no therapies tailored to metastatic disease. Despite the development of numerous treatment modalities targeting the primary tumor, 40% of pa- tients still die from metastatic progression. Developing targeted therapies for metastatic OS has been compli-

cated by extensive genomic rearrangements that differ across patients, but a common feature is that OS tends to metastasize to the lung. There is a pressing clinical need to determine the factors responsible for lung me- tastasis in OS to facilitate development of novel antimetastatic therapies. Previous findings have demonstrated

the importance of alterations in enhancer activity and specific transcription factors in activating genes necessary for metastasis. However, recent studies on epigenetic subtypes of OS suggest that many of the models studied previously diverge from the epigenetic subtype of this disease most common and most deadly in the clinic.

Here we propose in aim 1 to study the transcription factors (RUNX2 and SP7) that are specific to the subtype of OS that is most clinically relevant, and we plan to characterize how these create: de novo enhancer activation, novel loops and clusters in cis and trans, and novel enhancer-gene connections that promote lung metastasis.

Our goal is to define “metastasis enabling circuitry”. Aim 2 tests the hypothesis that the process of lung coloni- zation is driven by an interplay between RUNX2 and signaling from the lung microenvironment through a longi- tudinal series of dynamic chromatin state changes, each with unique gene dependencies. We seek to understand

the biology of the metastatic process by charting the chromatin state transitions and dependencies in osteosar- coma cells growing within the in vivo context of the lung microenvironment. If successful, we hope to expand the current arsenal of OS treatments beyond coverage of the primary lesion, to target tumor metastases during lung

colonization.