The impact of osteoblastic differentiation on osteosarcomagenesis in the mouse

Quist, Tyler S.; Jin, Huifeng; Zhu, Ju-Fen; Smith-Fry, Kyllie; Capecchi, Mario R.; Jones, Kevin B.

doi:10.1038/onc.2014.354

Cited by 49 publications

(56 citation statements)

References 34 publications

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“…Although Osteocalcin-expressing osteoblasts are thought to be non-cycling, they do form tumors upon p53 and Rb1 deletion (36). Our report is the first showing that deletion of p53 in mature osteoblasts ( p53 Δoc ) is associated with high-grade OS.…”

Section: Discussionmentioning

confidence: 99%

WWOX and p53 Dysregulation Synergize to Drive the Development of Osteosarcoma

et al. 2016

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Osteosarcoma (OS) is a highly metastatic form of bone cancer in adolescents and young adults which 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 pre-osteoblasts (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 OS in histology, location, metastatic behavior, and gene expression. Strikingly, the development of osteosarcomas in these mice was greatly accelerated compared to mice lacking p53 only. In contrast, combined WWOX and p53 inactivation in mature osteoblasts did not accelerate osteosarcomagenesis compared to 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 OS. The Wwox;p53Δosx1 double knockout establishes a new OS model with significant advancement over existing models.

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Section: Discussionmentioning

confidence: 99%

WWOX and p53 Dysregulation Synergize to Drive the Development of Osteosarcoma

et al. 2016

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“…In mouse models (Figure 1), osteoblastic OS can be efficiently initiated by one driver, such as p53 (loss of two alleles) [17], or by two drivers, such as the Ptch1 (loss of one allele) and p53 (loss of one allele) with about 70% penetrance [67]. Fibroblastic OS can be efficiently initiated by one driver, such as Notch [16], or by two drivers, such as p53 (loss of two alleles) and Rb1 (loss of two alleles) [17, 21, 23]. In the latter case, the Rb1 driver not only accelerates tumor development, but also switches tumor subtype from osteoblastic to fibroblastic.…”

Section: Understanding the Role Of Driver Gene Mutations In The Dementioning

confidence: 99%

Molecular genetics of osteosarcoma

Rickel

Fang

Tao

2017

Bone

206

179

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Osteosarcoma is the predominant form of bone cancer, affecting mostly adolescents. Recent progress made in molecular genetic studies of osteosarcoma has changed our view on the cause of the disease and ongoing therapeutic approaches for patients. As we draw closer to gaining more complete catalogues of candidate cancer driver genes in common forms of cancer, the landscape of somatic mutations in osteosarcoma is emerging from its first phase. In this review, we summarize recent whole genome and/or whole exome genomic studies, and then put these findings in the context of genetic hallmarks of somatic mutations and mutational processes in human osteosarcoma. One of the lessons learned here is that the extent of somatic mutations and complexity of the osteosarcoma genome are similar to that of common forms of adult cancer. Thus, a much higher number of samples than those currently obtained are needed to complete the catalogue of driver mutations in human osteosarcoma. In parallel, genetic studies in other species have revealed candidate driver genes and their roles in the genesis of osteosarcoma. This review also summarizes newly identified drivers in genetically engineered mouse models (GEMMs) and discusses our understanding of the impact of nature and number of drivers on tumor latency, subtypes, and metastatic potentials of osteosarcoma. It is becoming apparent that a synergistic team composed of three drivers (one ‘first driver’ and two ‘synergistic drivers’) may be required to generate an animal model that recapitulates aggressive osteosarcoma with a short latency. Finally, new cancer therapies are urgently needed to improve survival rate and quality of life for osteosarcoma patients. Several vulnerabilities in osteosarcoma are illustrated in this review to exemplify the opportunities for next generation molecularly targeted therapies. However, much work remains in order to complete our understanding of the somatic mutation basis of osteosarcoma, to develop reliable animal models of human disease, and to apply this information to guide new therapeutic approaches for reducing morbidity and mortality of this rare disease.

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“…Tumor and matched normal bone tissue samples were obtained from mice homozygous for conditionally disrupted alleles of Trp53 and Rb1 , induced by Prx1Cre as described previously [59]. Schematic representation for generation of (Prx1Cre;Rb1-fl/fl;Trp53-fl/fl) osteosarcoma in mice homozygous for conditionally disrupted alleles of Trp53 and Rb1 is given is Supplementary Figure 3.…”

Section: Methodsmentioning

confidence: 99%

Imprinting defects at human 14q32 locus alters gene expression and is associated with the pathobiology of osteosarcoma

Shu

Sarver

et al. 2016

Oncotarget

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Osteosarcoma is the most common primary bone malignancy affecting children and adolescents. Although several genetic predisposing conditions have been associated with osteosarcoma, our understanding of its pathobiology is rather limited. Here we show that, first, an imprinting defect at human 14q32-locus is highly prevalent (87%) and specifically associated with osteosarcoma patients < 30 years of age. Second, the average demethylation at differentially methylated regions (DMRs) in the 14q32-locus varied significantly compared to genome-wide demethylation. Third, the 14q32-locus was enriched in both H3K4-me3 and H3K27-me3 histone modifications that affected expression of all imprinted genes and miRNAs in this region. Fourth, imprinting defects at 14q32 - DMRs are present in triad DNA samples from affected children and their biological parents. Finally, imprinting defects at 14q32-DMRs were also observed at higher frequencies in an Rb1/Trp53 mutation-induced osteosarcoma mouse model. Further analysis of normal and tumor tissues from a Sleeping Beauty mouse model of spontaneous osteosarcoma supported the notion that these imprinting defects may be a key factor in osteosarcoma pathobiology. In conclusion, we demonstrate that imprinting defects at the 14q32 locus significantly alter gene expression, may contribute to the pathogenesis of osteosarcoma, and could be predictive of survival outcomes.

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The impact of osteoblastic differentiation on osteosarcomagenesis in the mouse

Cited by 49 publications

References 34 publications

WWOX and p53 Dysregulation Synergize to Drive the Development of Osteosarcoma

WWOX and p53 Dysregulation Synergize to Drive the Development of Osteosarcoma

Molecular genetics of osteosarcoma

Imprinting defects at human 14q32 locus alters gene expression and is associated with the pathobiology of osteosarcoma

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