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Significance Li–Fraumeni syndrome is a rare disorder caused by germlineTP53 mutations, predisposing patients to early-onset cancers, including osteosarcoma (OS). Here we demonstrate that strong expression of SFRP2, a reported WNT antagonist, in OS patient samples correlates with poor survival and that SFRP2 overexpression suppresses normal osteoblast differentiation, promotes OS features, and facilitates angiogenesis via autocrine and paracrine mechanisms in an induced pluripotent stem cell disease model. We show that these SFRP2-mediated phenotypes are canonical WNT/β-catenin independent and are mediated through induction of oncogenes such as FOXM1 and CYR61. We further demonstrate that inhibition of SFRP2, FOXM1, or CYR61 represses tumorigenesis. Our data suggest that inhibition of SFRP2 should be explored clinically as a strategy for treatment patients with p53 mutation-associated OS.

Oncogenic role of SFRP2 in p53-mutant osteosarcoma development via autocrine and paracrine mechanism