Limits...
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

Orthotopic xenograft MPNSTs maintain the genomic structure found in primary tumorsGenome-wide SNP array profiling from two different orthoxenograft tumors derived from the same primary tumor (MPNST-NF1-001) are shown as Circos plots. The outermost layer contains the set of canonical human chromosomes. The following layers, from outside to inside, illustrate the following: the BAF of the primary tumor (A), and the derived xenografts at passages 1 (B and C) and 4 (D and E). Copy number variations are represented by a colored line under each BAF (gray: 2n, red: > 2n (chromosomal gain); green: < 2n (chromosomal loss)). LOH events are shown in blue. Finally, differences between primary and xenograft tumors not compatible with the loss of signal from stroma cells are highlighted in orange.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4492820&req=5

fig04: Orthotopic xenograft MPNSTs maintain the genomic structure found in primary tumorsGenome-wide SNP array profiling from two different orthoxenograft tumors derived from the same primary tumor (MPNST-NF1-001) are shown as Circos plots. The outermost layer contains the set of canonical human chromosomes. The following layers, from outside to inside, illustrate the following: the BAF of the primary tumor (A), and the derived xenografts at passages 1 (B and C) and 4 (D and E). Copy number variations are represented by a colored line under each BAF (gray: 2n, red: > 2n (chromosomal gain); green: < 2n (chromosomal loss)). LOH events are shown in blue. Finally, differences between primary and xenograft tumors not compatible with the loss of signal from stroma cells are highlighted in orange.

Mentions: We first analyzed tumor MPNST-NF1-001 by comparing the primary tumor with the orthoxenografts at passages 1 and 4 from two lineages representing two independent engraftments (Fig4). SNP array data from these five samples were analyzed using ASCAT. Comparison of the primary tumor with the four orthoxenografts allowed us to detect genomic alterations along xenograft passages, assessing the genomic stability of the engrafted tumor, and differences between two primary engrafted independent lineages, assessing the reproducibility of the orthoxenograft model. As expected, the genome of the primary MPNSTs and orthoxenografts was highly altered, mainly presenting gains of whole chromosomes or large chromosomal regions and a few losses of genetic material. In addition, B-allelle frequency (BAF) plots showed several patterns consistent with complex rearrangements and large regions exhibiting LOH (Fig4). A global view of the genomic alteration profiles showed a high degree of similarity between the primary tumor and the 4 derived orthoxenografts. In this case, due to the high proportion of non-altered stroma cells in the primary tumor sample, the raw data were strongly biased toward a diploid heterozygous genome; hence, the variant calling algorithm used reported fewer alterations in the primary tumor than in orthoxenografts. However, visual inspection of the raw data revealed that almost all alterations identified in orthoxenografts were present in primary tumors (see Fig4). Furthermore, these differences were not present in the rest of the primary tumor versus orthoxenograft comparisons, since these tumors contained a lower proportion of 2n cells (Supplementary Fig S4A and B). The comparison of BAF plots between primary tumor and orthoxenograft passages 1 and 4 was consistent with the progressive depletion of human 2n cells along passages. In addition, the analysis of multiple orthoxenograft passages revealed that this highly altered genome remained stable along successive xenograft passages (Supplementary Fig S4A and B). The differences in BAF between orthoxenografts at passage 1 and passage 4 that were not compatible with progressive stromal removal were interpreted as structural genomic changes caused by the successive engraftments (highlighted in Supplementary Fig S4A and B). Overall, comparative analysis of the primary tumor and the serial passages of the orthoxenograft models indicated that, on average, < 7% of the orthoxenograft genome presented structural changes (copy number alterations and allelic imbalances) relative to the primary tumor.


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)

Orthotopic xenograft MPNSTs maintain the genomic structure found in primary tumorsGenome-wide SNP array profiling from two different orthoxenograft tumors derived from the same primary tumor (MPNST-NF1-001) are shown as Circos plots. The outermost layer contains the set of canonical human chromosomes. The following layers, from outside to inside, illustrate the following: the BAF of the primary tumor (A), and the derived xenografts at passages 1 (B and C) and 4 (D and E). Copy number variations are represented by a colored line under each BAF (gray: 2n, red: > 2n (chromosomal gain); green: < 2n (chromosomal loss)). LOH events are shown in blue. Finally, differences between primary and xenograft tumors not compatible with the loss of signal from stroma cells are highlighted in orange.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig04: Orthotopic xenograft MPNSTs maintain the genomic structure found in primary tumorsGenome-wide SNP array profiling from two different orthoxenograft tumors derived from the same primary tumor (MPNST-NF1-001) are shown as Circos plots. The outermost layer contains the set of canonical human chromosomes. The following layers, from outside to inside, illustrate the following: the BAF of the primary tumor (A), and the derived xenografts at passages 1 (B and C) and 4 (D and E). Copy number variations are represented by a colored line under each BAF (gray: 2n, red: > 2n (chromosomal gain); green: < 2n (chromosomal loss)). LOH events are shown in blue. Finally, differences between primary and xenograft tumors not compatible with the loss of signal from stroma cells are highlighted in orange.
Mentions: We first analyzed tumor MPNST-NF1-001 by comparing the primary tumor with the orthoxenografts at passages 1 and 4 from two lineages representing two independent engraftments (Fig4). SNP array data from these five samples were analyzed using ASCAT. Comparison of the primary tumor with the four orthoxenografts allowed us to detect genomic alterations along xenograft passages, assessing the genomic stability of the engrafted tumor, and differences between two primary engrafted independent lineages, assessing the reproducibility of the orthoxenograft model. As expected, the genome of the primary MPNSTs and orthoxenografts was highly altered, mainly presenting gains of whole chromosomes or large chromosomal regions and a few losses of genetic material. In addition, B-allelle frequency (BAF) plots showed several patterns consistent with complex rearrangements and large regions exhibiting LOH (Fig4). A global view of the genomic alteration profiles showed a high degree of similarity between the primary tumor and the 4 derived orthoxenografts. In this case, due to the high proportion of non-altered stroma cells in the primary tumor sample, the raw data were strongly biased toward a diploid heterozygous genome; hence, the variant calling algorithm used reported fewer alterations in the primary tumor than in orthoxenografts. However, visual inspection of the raw data revealed that almost all alterations identified in orthoxenografts were present in primary tumors (see Fig4). Furthermore, these differences were not present in the rest of the primary tumor versus orthoxenograft comparisons, since these tumors contained a lower proportion of 2n cells (Supplementary Fig S4A and B). The comparison of BAF plots between primary tumor and orthoxenograft passages 1 and 4 was consistent with the progressive depletion of human 2n cells along passages. In addition, the analysis of multiple orthoxenograft passages revealed that this highly altered genome remained stable along successive xenograft passages (Supplementary Fig S4A and B). The differences in BAF between orthoxenografts at passage 1 and passage 4 that were not compatible with progressive stromal removal were interpreted as structural genomic changes caused by the successive engraftments (highlighted in Supplementary Fig S4A and B). Overall, comparative analysis of the primary tumor and the serial passages of the orthoxenograft models indicated that, on average, < 7% of the orthoxenograft genome presented structural changes (copy number alterations and allelic imbalances) relative to the primary tumor.

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