WWOX and p53 dysregulation synergize to drive the development of osteosarcoma

Sara Del Mare, Hussam Husanie, Ortal Iancu, Mohammad Abu-Odeh, Konstantinos Evangelou, Francesca Lovat, Stefano Volinia, Jonathan Gordon, Gail Amir, Janet Stein, Gary S. Stein, Carlo M. Croce, Vassilis Gorgoulis, Jane B. Lian, Rami I. Aqeilan

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40 Scopus citations


Osteosarcoma is a highly metastatic form of bone cancer in adolescents and young adults that is resistant to existing treatments. Development of an effective therapy has been hindered by very limited understanding of the mechanisms of osteosarcomagenesis. Here, we used genetically engineered mice to investigate the effects of deleting the tumor suppressor Wwox selectively in either osteoblast progenitors or mature osteoblasts. Mice with conditional deletion of Wwox in preosteoblasts (WwoxΔosx1) displayed a severe inhibition of osteogenesis accompanied by p53 upregulation, effects that were not observed in mice lacking Wwox in mature osteoblasts. Deletion of p53 in WwoxΔosx1 mice rescued the osteogenic defect. In addition, the Wwox;p53Δosx1 double knockout mice developed poorly differentiated osteosarcomas that resemble human osteosarcoma in histology, location, metastatic behavior, and gene expression. Strikingly, the development of osteosarcomas in these mice was greatly accelerated compared with mice lacking p53 only. In contrast, combined WWOX and p53 inactivation in mature osteoblasts did not accelerate osteosarcomagenesis compared with p53 inactivation alone. These findings provide evidence that a WWOX-p53 network regulates normal bone formation and that disruption of this network in osteoprogenitors results in accelerated osteosarcoma. The Wwox;p53Δosx1 double knockout establishes a new osteosarcoma model with significant advancement over existing models.

Original languageEnglish
Pages (from-to)6107-6117
Number of pages11
JournalCancer Research
Issue number20
StatePublished - 15 Oct 2016
Externally publishedYes

Bibliographical note

Publisher Copyright:
©2016 AACR.


We are grateful for the Aqeilan lab members for fruitful discussions. This work was supported in part by the BSF grant (#2011300) to R.I. Aqeilan, J.B. Lian, G.S. Stein, and J. Stein, by ICRF grant to R.I. Aqeilan, by P01 Cancer grant P01 CA82834 NIH/NCI to G.S. Stein, and R37 DE012528 NIH/NIDCR to J.B. Lian. V. Gorgoulis and K. Evangelou are financially supported by the Greek GSRT Program of Excellence II (Aristeia II). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

FundersFunder number
Greek GSRT Program of Excellence II
National Institute of Dental and Craniofacial ResearchR37DE012528
Israel Cancer Research FundR37 DE012528 NIH/NIDCR, P01 CA82834 NIH/NCI
United States-Israel Binational Science Foundation2011300


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