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PRRX1 is a master transcription factor of stromal fibroblasts for myofibroblastic lineage progression

Author

Listed:
  • Keun-Woo Lee

    (Sungkyunkwan University)

  • So-Young Yeo

    (Sungkyunkwan University)

  • Jeong-Ryeol Gong

    (Korea Advanced Institute of Science and Technology)

  • Ok-Jae Koo

    (Geumcheon)

  • Insuk Sohn

    (Gangnam-daero)

  • Woo Yong Lee

    (Sungkyunkwan University School of Medicine)

  • Hee Cheol Kim

    (Sungkyunkwan University School of Medicine)

  • Seong Hyeon Yun

    (Sungkyunkwan University School of Medicine)

  • Yong Beom Cho

    (Sungkyunkwan University School of Medicine)

  • Mi-Ae Choi

    (Sungkyunkwan University)

  • Sugyun An

    (Korea Advanced Institute of Science and Technology)

  • Juhee Kim

    (Korea Advanced Institute of Science and Technology)

  • Chang Ohk Sung

    (University of Ulsan College of Medicine)

  • Kwang-Hyun Cho

    (Korea Advanced Institute of Science and Technology)

  • Seok-Hyung Kim

    (Sungkyunkwan University
    Sungkyunkwan University School of Medicine
    Sungkyunkwan University School of Medicine)

Abstract

Although stromal fibroblasts play a critical role in cancer progression, their identities remain unclear as they exhibit high heterogeneity and plasticity. Here, a master transcription factor (mTF) constructing core-regulatory circuitry, PRRX1, which determines the fibroblast lineage with a myofibroblastic phenotype, is identified for the fibroblast subgroup. PRRX1 orchestrates the functional drift of fibroblasts into myofibroblastic phenotype via TGF-β signaling by remodeling a super-enhancer landscape. Such reprogrammed fibroblasts have myofibroblastic functions resulting in markedly enhanced tumorigenicity and aggressiveness of cancer. PRRX1 expression in cancer-associated fibroblast (CAF) has an unfavorable prognosis in multiple cancer types. Fibroblast-specific PRRX1 depletion induces long-term and sustained complete remission of chemotherapy-resistant cancer in genetically engineered mice models. This study reveals CAF subpopulations based on super-enhancer profiles including PRRX1. Therefore, mTFs, including PRRX1, provide another opportunity for establishing a hierarchical classification system of fibroblasts and cancer treatment by targeting fibroblasts.

Suggested Citation

  • Keun-Woo Lee & So-Young Yeo & Jeong-Ryeol Gong & Ok-Jae Koo & Insuk Sohn & Woo Yong Lee & Hee Cheol Kim & Seong Hyeon Yun & Yong Beom Cho & Mi-Ae Choi & Sugyun An & Juhee Kim & Chang Ohk Sung & Kwang-, 2022. "PRRX1 is a master transcription factor of stromal fibroblasts for myofibroblastic lineage progression," Nature Communications, Nature, vol. 13(1), pages 1-23, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30484-4
    DOI: 10.1038/s41467-022-30484-4
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    References listed on IDEAS

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