Vascular Tumor Recapitulated in Endothelial Cells from hiPSCs Engineered to Express the SERPINE1-FOSB Translocation.
Cell Rep Med
; 1(9): 100153, 2020 12 22.
Article
em En
| MEDLINE
| ID: mdl-33377124
ABSTRACT
Chromosomal translocations are prevalent among soft tissue tumors, including those of the vasculature such as pseudomyogenic hemangioendothelioma (PHE). PHE shows endothelial cell (EC) features and has a tumor-specific t(7;19)(q22;q13) SERPINE1-FOSB translocation, but is difficult to study as no primary tumor cell lines have yet been derived. Here, we engineer the PHE chromosomal translocation into human induced pluripotent stem cells (hiPSCs) using CRISPR/Cas9 and differentiate these into ECs (hiPSC-ECs) to address this. Comparison of parental with PHE hiPSC-ECs shows (1) elevated expression of FOSB, (2) higher proliferation and more tube formation but lower endothelial barrier function, (3) invasive growth and abnormal vessel formation in mice after transplantation, and (4) specific transcriptome alterations reflecting PHE and indicating PI3K-Akt and MAPK signaling pathways as possible therapeutic targets. The modified hiPSC-ECs thus recapitulate functional features of PHE and demonstrate how these translocation models can be used to understand tumorigenic mechanisms and identify therapeutic targets.
Palavras-chave
CRISPR/Cas9-mediated gene targeting; PHE; chromosomal translocation; endothelial cell differentiation; gene fusion; hiPSC-ECs; hiPSC-derived ECs; hiPSCs; human induced pluripotent stem cells; pseudomyogenic hemangioendothelioma; t(7;19)(q22;q13) SERPINE1-FOSB chromosomal translocation; tumor model; vascular tumor
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas Proto-Oncogênicas c-fos
/
Inibidor 1 de Ativador de Plasminogênio
/
Células Endoteliais
/
Células-Tronco Pluripotentes Induzidas
Limite:
Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article