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

Huensuk Kim, Seungyeul Yoo, Ruoji Zhou, An Xu, Jeffrey M. Bernitz, Ye Yuan, Andreia M. Gomes, Michael G. Daniel, Jie Su, Elizabeth G. Demicco, Jun Zhu, Kateri A. Moore, Dung Fang Lee, Ihor R. Lemischka, Christoph Schaniel

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

Osteosarcoma (OS), the most common primary bone tumor, is highly metastatic with high chemotherapeutic resistance and poor survival rates. Using induced pluripotent stem cells (iPSCs) generated from Li–Fraumeni syndrome (LFS) patients, we investigate an oncogenic role of secreted frizzled-related protein 2 (SFRP2) in p53 mutation-associated OS development. Interestingly, we find that high SFRP2 expression in OS patient samples correlates with poor survival. Systems-level analyses identified that expression of SFRP2 increases during LFS OS development and can induce angiogenesis. Ectopic SFRP2 overexpression in normal osteoblast precursors is sufficient to suppress normal osteoblast differentiation and to promote OS phenotypes through induction of oncogenic molecules such as FOXM1 and CYR61 in a β-catenin–independent manner. Conversely, inhibition of SFRP2, FOXM1, or CYR61 represses the tumorigenic potential. In summary, these findings demonstrate the oncogenic role of SFRP2 in the development of p53 mutation-associated OS and that inhibition of SFRP2 is a potential therapeutic strategy.

Original languageEnglish
Pages (from-to)E11128-E11137
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number47
DOIs
StatePublished - 20 Nov 2018

Keywords

  • Autocrine
  • Osteosarcoma
  • P53
  • Paracrine
  • SFRP2

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