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

Author

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  • Miwa Tanaka

    (Division of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research
    Tokyo Medical University
    Project for Cancer Epigenomics, The Cancer Institute, Japanese Foundation for Cancer Research)

  • Surachada Chuaychob

    (Kyoto University)

  • Mizuki Homme

    (Division of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research
    Division of Cell Biology, The Cancer Institute, Japanese Foundation for Cancer Research)

  • Yukari Yamazaki

    (Division of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research
    Tokyo Medical University)

  • Ruyin Lyu

    (Kyoto University)

  • Kyoko Yamashita

    (Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research)

  • Keisuke Ae

    (Cancer Institute Hospital, Japanese Foundation for Cancer Research)

  • Seiichi Matsumoto

    (Cancer Institute Hospital, Japanese Foundation for Cancer Research)

  • Kohei Kumegawa

    (Project for Cancer Epigenomics, The Cancer Institute, Japanese Foundation for Cancer Research)

  • Reo Maruyama

    (Project for Cancer Epigenomics, The Cancer Institute, Japanese Foundation for Cancer Research)

  • Wei Qu

    (The University of Tokyo)

  • Yohei Miyagi

    (Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute)

  • Ryuji Yokokawa

    (Kyoto University)

  • Takuro Nakamura

    (Division of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research
    Tokyo Medical University)

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.

Suggested Citation

  • Miwa Tanaka & Surachada Chuaychob & Mizuki Homme & Yukari Yamazaki & Ruyin Lyu & Kyoko Yamashita & Keisuke Ae & Seiichi Matsumoto & Kohei Kumegawa & Reo Maruyama & Wei Qu & Yohei Miyagi & Ryuji Yokoka, 2023. "ASPSCR1::TFE3 orchestrates the angiogenic program of alveolar soft part sarcoma," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37049-z
    DOI: 10.1038/s41467-023-37049-z
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    References listed on IDEAS

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    1. Rene C. Adam & Hanseul Yang & Shira Rockowitz & Samantha B. Larsen & Maria Nikolova & Daniel S. Oristian & Lisa Polak & Meelis Kadaja & Amma Asare & Deyou Zheng & Elaine Fuchs, 2015. "Pioneer factors govern super-enhancer dynamics in stem cell plasticity and lineage choice," Nature, Nature, vol. 521(7552), pages 366-370, May.
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