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Comprehensive establishment and characterization of orthoxenograft mouse models of malignant peripheral nerve sheath tumors for personalized medicine.

Castellsagué J, Gel B, Fernández-Rodríguez J, Llatjós R, Blanco I, Benavente Y, Pérez-Sidelnikova D, García-Del Muro J, Viñals JM, Vidal A, Valdés-Mas R, Terribas E, López-Doriga A, Pujana MA, Capellá G, Puente XS, Serra E, Villanueva A, Lázaro C - EMBO Mol Med (2015)

Bottom Line: These aggressive malignancies confer poor survival, with no effective therapy available.Our work points to differences in the engraftment process of primary tumors compared with the engraftment of established cell lines.Sorafenib (a BRAF inhibitor), in combination with doxorubicin or rapamycin, was found to be the most effective treatment for reducing MPNST growth.

View Article: PubMed Central - PubMed

Affiliation: Hereditary Cancer Program, Catalan Institute of Oncology (ICO-IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain Translational Research Laboratory ICO-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.

No MeSH data available.


Related in: MedlinePlus

Gene expression profiles between primary and orthotopic xenograft MPNSTs are similarHeat map showing the correlations between expression levels of genes in the molecular signature of MPNSTs.Hierarchical clustering of tumors and xenografts groups all primary tumors with their derived orthoxenografts. Moreover, sporadic tumors and NF1-related tumors form two different clusters.PCA of genes in the molecular signature of MPNSTs. All primary-xenograft pairs cluster together. The first component distinguishes between sporadic and NF1-related tumors; the second component differentiates primary tumors (and derived orthoxenografts) from the cell line (and the derived orthoxenograft).
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fig06: Gene expression profiles between primary and orthotopic xenograft MPNSTs are similarHeat map showing the correlations between expression levels of genes in the molecular signature of MPNSTs.Hierarchical clustering of tumors and xenografts groups all primary tumors with their derived orthoxenografts. Moreover, sporadic tumors and NF1-related tumors form two different clusters.PCA of genes in the molecular signature of MPNSTs. All primary-xenograft pairs cluster together. The first component distinguishes between sporadic and NF1-related tumors; the second component differentiates primary tumors (and derived orthoxenografts) from the cell line (and the derived orthoxenograft).

Mentions: Gene expression levels are influenced by different biological processes at the genomic and epigenomic levels. Thus, gene expression analysis can provide an integrative and more functional overview of the state of a tumor. Accordingly, expression array analysis was performed to validate the orthoxenograft models at the gene expression level. We observed a high global correlation between the normalized expression values for primary tumors and orthoxenografts at passage 1 (R2 ~0.9) and an even higher correlation between the values at passage 1 and passage 4 (R2 ~0.98), which is consistent with the removal of stromal cells (Fig6). We then analyzed a subset of ~1,000 genes representing a molecular signature associated with NF1-peripheral nerve sheath tumors, differentiating benign tumors from malignant tumors and derived cell lines (Miller et al, 2009). Using this signature, the analysis reported an even closer correlation between orthoxenografts and the corresponding primary tumors (R2 ~0.95); by contrast, using the same signature, lower correlation values were reported between distinct primary tumors (R2 ~0.78) and between primary tumors and non-corresponding xenografts (R2 ~0.8) (Fig6A). Unsupervised clustering analysis organized all of the samples analyzed, with each primary tumor grouped with the corresponding derived orthoxenografts at different passages (Fig6B). This analysis also classified the samples in two groups: NF1-related (including the S462 cell line and derived xenograft) and sporadic cases (Fig6B). This classification was obtained using both the molecular signature for NF1-related MPNST and the whole expression profile.


Comprehensive establishment and characterization of orthoxenograft mouse models of malignant peripheral nerve sheath tumors for personalized medicine.

Castellsagué J, Gel B, Fernández-Rodríguez J, Llatjós R, Blanco I, Benavente Y, Pérez-Sidelnikova D, García-Del Muro J, Viñals JM, Vidal A, Valdés-Mas R, Terribas E, López-Doriga A, Pujana MA, Capellá G, Puente XS, Serra E, Villanueva A, Lázaro C - EMBO Mol Med (2015)

Gene expression profiles between primary and orthotopic xenograft MPNSTs are similarHeat map showing the correlations between expression levels of genes in the molecular signature of MPNSTs.Hierarchical clustering of tumors and xenografts groups all primary tumors with their derived orthoxenografts. Moreover, sporadic tumors and NF1-related tumors form two different clusters.PCA of genes in the molecular signature of MPNSTs. All primary-xenograft pairs cluster together. The first component distinguishes between sporadic and NF1-related tumors; the second component differentiates primary tumors (and derived orthoxenografts) from the cell line (and the derived orthoxenograft).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492820&req=5

fig06: Gene expression profiles between primary and orthotopic xenograft MPNSTs are similarHeat map showing the correlations between expression levels of genes in the molecular signature of MPNSTs.Hierarchical clustering of tumors and xenografts groups all primary tumors with their derived orthoxenografts. Moreover, sporadic tumors and NF1-related tumors form two different clusters.PCA of genes in the molecular signature of MPNSTs. All primary-xenograft pairs cluster together. The first component distinguishes between sporadic and NF1-related tumors; the second component differentiates primary tumors (and derived orthoxenografts) from the cell line (and the derived orthoxenograft).
Mentions: Gene expression levels are influenced by different biological processes at the genomic and epigenomic levels. Thus, gene expression analysis can provide an integrative and more functional overview of the state of a tumor. Accordingly, expression array analysis was performed to validate the orthoxenograft models at the gene expression level. We observed a high global correlation between the normalized expression values for primary tumors and orthoxenografts at passage 1 (R2 ~0.9) and an even higher correlation between the values at passage 1 and passage 4 (R2 ~0.98), which is consistent with the removal of stromal cells (Fig6). We then analyzed a subset of ~1,000 genes representing a molecular signature associated with NF1-peripheral nerve sheath tumors, differentiating benign tumors from malignant tumors and derived cell lines (Miller et al, 2009). Using this signature, the analysis reported an even closer correlation between orthoxenografts and the corresponding primary tumors (R2 ~0.95); by contrast, using the same signature, lower correlation values were reported between distinct primary tumors (R2 ~0.78) and between primary tumors and non-corresponding xenografts (R2 ~0.8) (Fig6A). Unsupervised clustering analysis organized all of the samples analyzed, with each primary tumor grouped with the corresponding derived orthoxenografts at different passages (Fig6B). This analysis also classified the samples in two groups: NF1-related (including the S462 cell line and derived xenograft) and sporadic cases (Fig6B). This classification was obtained using both the molecular signature for NF1-related MPNST and the whole expression profile.

Bottom Line: These aggressive malignancies confer poor survival, with no effective therapy available.Our work points to differences in the engraftment process of primary tumors compared with the engraftment of established cell lines.Sorafenib (a BRAF inhibitor), in combination with doxorubicin or rapamycin, was found to be the most effective treatment for reducing MPNST growth.

View Article: PubMed Central - PubMed

Affiliation: Hereditary Cancer Program, Catalan Institute of Oncology (ICO-IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain Translational Research Laboratory ICO-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.

No MeSH data available.


Related in: MedlinePlus