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- Title
PRRX1 is a master transcription factor of stromal fibroblasts for myofibroblastic lineage progression.
- Authors
Lee, Keun-Woo; Yeo, So-Young; Gong, Jeong-Ryeol; Koo, Ok-Jae; Sohn, Insuk; Lee, Woo Yong; Kim, Hee Cheol; Yun, Seong Hyeon; Cho, Yong Beom; Choi, Mi-Ae; An, Sugyun; Kim, Juhee; Sung, Chang Ohk; Cho, Kwang-Hyun; Kim, Seok-Hyung
- 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. Cancer associated fibroblasts are an important and highly heterogeneous component of the tumor microenvironment. Here the authors identify PRRX1 as a master transcription factor determining a fibroblast lineage with myofibroblastic phenotype, associated with unfavourable prognosis in several cancer types.
- Subjects
TRANSCRIPTION factors; FIBROBLASTS; MYOFIBROBLASTS; CANCER remission; TUMOR microenvironment; CANCER invasiveness
- Publication
Nature Communications, 2022, Vol 13, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-022-30484-4