Project Summary This Diversity Supplement application builds on a parental grant studying the genetic alterations at the RB transcriptional corepressor 1 (RB1) gene that are associated with increased mortality, metastasis and poor response to chemotherapy in osteosarcoma. We recently identified ubiquitin-like, containing PHD and RING finger domains-1 (UHRF1), as a key epigenetic regulator that is upregulated in osteosarcoma. Our preliminary studies suggest that UHRF1 overexpression results in increased cell proliferation, migration, invasion, and metastasis. For this supplement, we propose to expand the scope of our parental grant to elucidate the mechanisms through which UHRF1 overexpression in osteosarcoma contributes to tumor invasion and metastasis. We propose to examine the role of UHRF1 on the interaction between cancer cells and the tumor microenvironment through exosome alterations. Exosomes have been identified as an important factor in the modulation of cancer and stromal cells towards induction of a metastatic phenotype. We hypothesize that UHRF1 overexpression contributes to altered exosome formation and/or exosomal cargo and this contributes to metastasis in osteosarcoma. Overall, this research proposal will broaden our understanding of the role of UHRF1 in osteosarcoma metastasis.