Critical role for the TGF-β1/mTORC1 signaling axis in defining the transcriptional identity of CTHRC1 + pathologic fibroblasts

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Abstract
Fibrosis, marked by excess extracellular matrix (ECM) deposition, is the end stage of many diseases. Single-cell studies have highlighted the emergence of disease-specific fibroblast populations, including a high collagen–synthesizing CTHRC1 + subpopulation. The profibrotic cytokine TGF-β1 promotes fibrogenesis via cooperation between Smad and mTORC1/4E-BP1 signaling axes. Using CRISPR-Cas9 gene editing, we report that more than one-third of TGF-β1–regulated matrisome genes are under mTORC1 control. Mapping the transcriptome of TGF-β1–stimulated fibroblasts revealed similarity to CTHRC1 + fibroblasts identified in idiopathic pulmonary fibrosis (IPF). This overlap is lost when mTORC1 is disabled. Using the selective mTORC1 inhibitor RMC-5552, we confirm a causal role for mTORC1 in promoting the acquisition of the collagen-high, CTHRC1 + phenotype in response to TGF-β1 stimulation in fibroblasts derived from patients with either IPF or lung adenocarcinoma. We conclude that mTORC1 plays a key role in shaping the transcriptional identity of these fibroblasts, with implications for therapeutic inhibition of mTORC1 in fibrosis and cancer.
Funding Information
  • Cancer Research UK (C11496/A17786)
  • Cancer Research UK (C11496/A17786)
  • UK Research and Innovation/Medical Research Council UCL and Birkbeck Doctoral Training Programme (MR/N013867/1)
  • Biotechnology and Biological Sciences Research Council (BB/P504440/1)
  • Rosetrees Trust (M904)
  • Asthma and Lung UK
  • Asthma and Lung UK
  • National Institute for Health Research University College London Hospitals Biomedical Research Centre
  • National Institute for Health Research University College London Hospitals Biomedical Research Centre
  • UK Research and Innovation/Medical Research Council UCL and Birkbeck Doctoral Training Programme (MR/N013867/1)
  • Asthma and Lung UK (ECSG24\50)
  • Rosetrees Trust (M904)
  • Asthma and Lung UK (ECSG24\50)
  • UCL Therapeutic Acceleration Support scheme/MRC IAA 2021 (UCL MR/X502984/1)
  • Asthma and Lung UK (ECSG24\50)

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