A molecular map of mesenchymal tumors

Henderson, Stephen; Guiliano, David B.; Presneau, Nadège; McLean, Sean R.; Frow, Richard; Vujovic, Sonja; Anderson, John; Sebire, Neil J.; Whelan, Jeremy; Athanasou, Nick; Flanagan, Adrienne M.; Boshoff, Chris

doi:10.1186/gb-2005-6-9-r76

Cited by 123 publications

(50 citation statements)

References 49 publications

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“…The phenotype of the tumors originating from the 5-hits cell line was confirmed by comparing their GEM profiles to those of 96 different human sarcomas using a subset of genes previously identified as a molecular fingerprint for sarcoma (23). Multidimensional scaling demonstrated that the tumors generated in mice from MSC all cluster with the spindle-cell sarcoma group (Fig.…”

Section: Resultsmentioning

confidence: 87%

Transformation of human mesenchymal stem cells increases their dependency on oxidative phosphorylation for energy production

Funes

Quintero

Henderson

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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An increased dependency on glycolysis for ATP production is considered to be a hallmark of tumor cells. Whether this increase in glycolytic activity is due mainly to inherent metabolic alterations or to the hypoxic microenvironment remains controversial. Here we have transformed human adult mesenchymal stem cells (MSC) using genetic alterations as described for differentiated cells. Our data suggest that MSC require disruption of the same pathways as have been shown for differentiated cells to confer a fully transformed phenotype. Furthermore, we found that MSC are more glycolytic than primary human fibroblasts and, in contrast to differentiated cells, do not depend on increased aerobic glycolysis for ATP production during transformation. These data indicate that aerobic glycolysis (the Warburg effect) is not an intrinsic component of the transformation of adult stem cells, and that oncogenic adaptation to bioenergetic requirements, in some circumstances, may also rely on increases in oxidative phosphorylation. We did find, however, a reversible increase in the transcription of glycolytic enzymes in tumors generated by transformed MSC, indicating this is a secondary phenomenon resulting from adaptation of the tumor to its microenvironment. adult stem cells ͉ glycolysis ͉ Warburg effect

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Section: Resultsmentioning

confidence: 87%

Transformation of human mesenchymal stem cells increases their dependency on oxidative phosphorylation for energy production

Funes

Quintero

Henderson

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

229

220

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“…To define the metagene for human OS, we utilized a previously published set of human sarcoma data (Henderson et al 2005). This data set contained 11 OS samples, as well as a variety of other defined human sarcoma types of mesenchymal origin.…”

Section: Recapitulation Of the Transcriptional Profile Of Human Osmentioning

confidence: 99%

“…mode=view&paper_id=161. Human sarcoma data were obtained from a previously published data set (Henderson et al 2005).…”

Section: Metagene Analysismentioning

confidence: 99%

Conditional mouse osteosarcoma, dependent on p53 loss and potentiated by loss of Rb, mimics the human disease

Walkley

Qudsi²,

Sankaran³

et al. 2008

Genes Dev.

333

370

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Osteosarcoma is the most common primary malignant tumor of bone. Analysis of familial cancer syndromes and sporadic cases has strongly implicated both p53 and pRb in its pathogenesis; however, the relative contribution of these mutations to the initiation of osteosarcoma is unclear. We describe here the generation and characterization of a genetically engineered mouse model in which all animals develop short latency malignant osteosarcoma. The genetically engineered mouse model is based on osteoblast-restricted deletion of p53 and pRb. Osteosarcoma development is dependent on loss of p53 and potentiated by loss of pRb, revealing a dominance of p53 mutation in the development of osteosarcoma. The model reproduces many of the defining features of human osteosarcoma including cytogenetic complexity and comparable gene expression signatures, histology, and metastatic behavior. Using a novel in silico methodology termed cytogenetic region enrichment analysis, we demonstrate high conservation of gene expression changes between murine osteosarcoma and known cytogentically rearranged loci from human osteosarcoma. Due to the strong similarity between murine osteosarcoma and human osteosarcoma in this model, this should provide a valuable platform for addressing the molecular genetics of osteosarcoma and for developing novel therapeutic strategies.[Keywords: Cancer; mouse model; osteocarcinoma] Supplemental material is available at http://www.genesdev.org.

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“…Finally, we explored the relationship between differential DNAm and gene expression by integrating our DNAm data with published gene expression data from NFs and MPNSTs (Henderson et al 2005;Miller et al 2009). We next asked whether gene expression correlated sufficiently with aberrant DNAm to discriminate between benign and malignant disease phenotypes.…”

Section: à65mentioning

confidence: 99%

“…Gene expression analysis was performed using publically available data (MPNSTs, n = 10; NFs, n = 27) (Henderson et al 2005;Miller et al 2009). Gene expression data were derived from raw intensities using RMA (Irizarry et al 2003).…”

Section: Gene Expression Analysismentioning

confidence: 99%

Comparative methylome analysis of benign and malignant peripheral nerve sheath tumors

Feber

Wilson

Zhang³

et al. 2011

Genome Res.

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100

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Aberrant DNA methylation (DNAm) was first linked to cancer over 25 yr ago. Since then, many studies have associated hypermethylation of tumor suppressor genes and hypomethylation of oncogenes to the tumorigenic process. However, most of these studies have been limited to the analysis of promoters and CpG islands (CGIs). Recently, new technologies for whole-genome DNAm (methylome) analysis have been developed, enabling unbiased analysis of cancer methylomes. By using MeDIP-seq, we report a sequencing-based comparative methylome analysis of malignant peripheral nerve sheath tumors (MPNSTs), benign neurofibromas, and normal Schwann cells. Analysis of these methylomes revealed a complex landscape of DNAm alterations. In contrast to what has been reported for other tumor types, no significant global hypomethylation was observed in MPNSTs using methylome analysis by MeDIP-seq. However, a highly significant (P < 10−100) directional difference in DNAm was found in satellite repeats, suggesting these repeats to be the main target for hypomethylation in MPNSTs. Comparative analysis of the MPNST and Schwann cell methylomes identified 101,466 cancer-associated differentially methylated regions (cDMRs). Analysis showed these cDMRs to be significantly enriched for two satellite repeat types (SATR1 and ARLα) and suggests an association between aberrant DNAm of these sequences and transition from healthy cells to malignant disease. Significant enrichment of hypermethylated cDMRs in CGI shores (P < 10−60), non–CGI-associated promoters (P < 10−4) and hypomethylated cDMRs in SINE repeats (P < 10−100) was also identified. Integration of DNAm and gene expression data showed that the expression pattern of genes associated with CGI shore cDMRs was able to discriminate between disease phenotypes. This study establishes MeDIP-seq as an effective method to analyze cancer methylomes.

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A molecular map of mesenchymal tumors

Cited by 123 publications

References 49 publications

Transformation of human mesenchymal stem cells increases their dependency on oxidative phosphorylation for energy production

Transformation of human mesenchymal stem cells increases their dependency on oxidative phosphorylation for energy production

Conditional mouse osteosarcoma, dependent on p53 loss and potentiated by loss of Rb, mimics the human disease

Comparative methylome analysis of benign and malignant peripheral nerve sheath tumors

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