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

Abstract

<jats:title>Abstract</jats:title><jats:p>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, <jats:italic>PRRX1</jats:italic>, which determines the fibroblast lineage with a myofibroblastic phenotype, is identified for the fibroblast subgroup. <jats:italic>PRRX1</jats:italic> 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 <jats:italic>PRRX1</jats:italic> 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 <jats:italic>PRRX1</jats:italic>. Therefore, mTFs, including <jats:italic>PRRX1</jats:italic>, provide another opportunity for establishing a hierarchical classification system of fibroblasts and cancer treatment by targeting fibroblasts.</jats:p>