Vascular Tumor Recapitulated in Endothelial Cells from hiPSCs Engineered to Express the SERPINE1-FOSB Translocation

David G P van IJzendoorn, Daniela C F Salvatori, Xu Cao, Francijna van den Hil, Inge H Briaire-de Bruijn, Danielle de Jong, Hailiang Mei, Christine L Mummery, Karoly Szuhai, Judith V M G Bovée, Valeria V Orlova

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Article number100153
JournalCell reports. Medicine
Volume1
Issue number9
Early online date22 Dec 2020
DOIs
Publication statusPublished - 22 Dec 2020
Externally publishedYes

Keywords

  • Cell Differentiation/physiology
  • Endothelial Cells/metabolism
  • Humans
  • Induced Pluripotent Stem Cells/metabolism
  • Neoplasms, Vascular Tissue/metabolism
  • Plasminogen Activator Inhibitor 1/metabolism
  • Proto-Oncogene Proteins c-fos/genetics
  • Soft Tissue Neoplasms/metabolism
  • Translocation, Genetic/physiology
  • Vascular Neoplasms/metabolism

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