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

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-Hyun Cho () and Seok-Hyung Kim ()
Additional contact information
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

Nature Communications, 2022, vol. 13, issue 1, 1-23

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-30484-4

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