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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

Exome-sequencing analysisNumber of somatic point mutations identified in primary tumors and new mutations acquired in the orthoxenograft models in PRS-WCR. Somatic mutations found in primary tumors in sporadic cases were maintained in the orthoxenograft-derived tumors, whereas few acquired mutations were observed in all NF1-derived models. PT, primary tumor; OT, orthotopic xenograft tumor; passage 1 (P1); passage 4 (P4).
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fig05: Exome-sequencing analysisNumber of somatic point mutations identified in primary tumors and new mutations acquired in the orthoxenograft models in PRS-WCR. Somatic mutations found in primary tumors in sporadic cases were maintained in the orthoxenograft-derived tumors, whereas few acquired mutations were observed in all NF1-derived models. PT, primary tumor; OT, orthotopic xenograft tumor; passage 1 (P1); passage 4 (P4).

Mentions: The number of somatic mutations identified in PRS-WCR varied between PRSs and ranged from 22 in MPNST-NF1-002-PRS to 755 in MPNST-SP-001-PRS. When comparing tumors and xenograft pairs at passage 1, just after engraftment, a mean of ~9 (0–33) mutations was identified in orthoxenografts that were not present in primary tumors (Fig5) (Supplementary Table S1). New mutations were scattered over the genome and showed no apparent clustering except for three intronic mutations in the TTN gene. Of a total of 1,409 somatic mutations identified in the four primary tumors, only 6 (3 in MPNST-NF1-002-OT1 and 3 in MPNST-NF1-001-OT4) were not detected in the orthotopic xenograft models and therefore classified as lost in the engraftment process (data not shown). Altogether, the low number of new and lost point mutations detected in the engrafted tumors with respect to their primary counterparts reinforces our observation that the orthotopic xenograft MPNSTs generated for this study recapitulate the characteristics of the primary tumors.


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)

Exome-sequencing analysisNumber of somatic point mutations identified in primary tumors and new mutations acquired in the orthoxenograft models in PRS-WCR. Somatic mutations found in primary tumors in sporadic cases were maintained in the orthoxenograft-derived tumors, whereas few acquired mutations were observed in all NF1-derived models. PT, primary tumor; OT, orthotopic xenograft tumor; passage 1 (P1); passage 4 (P4).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig05: Exome-sequencing analysisNumber of somatic point mutations identified in primary tumors and new mutations acquired in the orthoxenograft models in PRS-WCR. Somatic mutations found in primary tumors in sporadic cases were maintained in the orthoxenograft-derived tumors, whereas few acquired mutations were observed in all NF1-derived models. PT, primary tumor; OT, orthotopic xenograft tumor; passage 1 (P1); passage 4 (P4).
Mentions: The number of somatic mutations identified in PRS-WCR varied between PRSs and ranged from 22 in MPNST-NF1-002-PRS to 755 in MPNST-SP-001-PRS. When comparing tumors and xenograft pairs at passage 1, just after engraftment, a mean of ~9 (0–33) mutations was identified in orthoxenografts that were not present in primary tumors (Fig5) (Supplementary Table S1). New mutations were scattered over the genome and showed no apparent clustering except for three intronic mutations in the TTN gene. Of a total of 1,409 somatic mutations identified in the four primary tumors, only 6 (3 in MPNST-NF1-002-OT1 and 3 in MPNST-NF1-001-OT4) were not detected in the orthotopic xenograft models and therefore classified as lost in the engraftment process (data not shown). Altogether, the low number of new and lost point mutations detected in the engrafted tumors with respect to their primary counterparts reinforces our observation that the orthotopic xenograft MPNSTs generated for this study recapitulate the characteristics of the primary tumors.

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