ASPSCR1::TFE3 orchestrates the angiogenic program of alveolar soft part sarcoma

Nat Commun. 2023 Apr 7;14(1):1957. doi: 10.1038/s41467-023-37049-z.

Abstract

Alveolar soft part sarcoma (ASPS) is a soft part malignancy affecting adolescents and young adults. ASPS is characterized by a highly integrated vascular network, and its high metastatic potential indicates the importance of ASPS's prominent angiogenic activity. Here, we find that the expression of ASPSCR1::TFE3, the fusion transcription factor causatively associated with ASPS, is dispensable for in vitro tumor maintenance; however, it is required for in vivo tumor development via angiogenesis. ASPSCR1::TFE3 is frequently associated with super-enhancers (SEs) upon its DNA binding, and the loss of its expression induces SE-distribution dynamic modification related to genes belonging to the angiogenesis pathway. Using epigenomic CRISPR/dCas9 screening, we identify Pdgfb, Rab27a, Sytl2, and Vwf as critical targets associated with reduced enhancer activities due to the ASPSCR1::TFE3 loss. Upregulation of Rab27a and Sytl2 promotes angiogenic factor-trafficking to facilitate ASPS vascular network construction. ASPSCR1::TFE3 thus orchestrates higher ordered angiogenesis via modulating the SE activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
  • Genes, Regulator
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Oncogene Proteins, Fusion* / genetics
  • Oncogene Proteins, Fusion* / metabolism
  • Sarcoma, Alveolar Soft Part* / diagnosis
  • Sarcoma, Alveolar Soft Part* / genetics
  • Sarcoma, Alveolar Soft Part* / pathology
  • Transcription Factors / genetics
  • Young Adult

Substances

  • Oncogene Proteins, Fusion
  • Transcription Factors
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • TFE3 protein, human
  • ASPSCR1 protein, human
  • Intracellular Signaling Peptides and Proteins