2. Academic Validation
  3. Fibroblast-derived EGF ligand Neuregulin-1 induces fetal-like reprogramming of the intestinal epithelium without supporting tumorigenic growth

Fibroblast-derived EGF ligand Neuregulin-1 induces fetal-like reprogramming of the intestinal epithelium without supporting tumorigenic growth

  • Dis Model Mech. 2023 Mar 13;dmm.049692. doi: 10.1242/dmm.049692.
Toni T Lemmetyinen 1,  Emma W Viitala 1,  Linnea Wartiovaara 1,  Tuomas Kaprio 1 2,  Jaana Hagström 1 3,  Caj Haglund 1 2,  Pekka Katajisto 4 5 6,  Timothy C Wang 7,  Eva Domènech-Moreno 8,  Saara Ollila 1
Affiliations

Affiliations

  • 1 Translational Cancer Medicine Program, University of Helsinki, Helsinki, Finland.
  • 2 Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
  • 3 Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki and Department of Oral Pathology and Radiology, University of Turku, Turku, Finland.
  • 4 Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland.
  • 5 Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
  • 6 Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland.
  • 7 Division of Digestive and Liver Diseases, Department of Medicine, Irving Cancer Research Center, Columbia University Medical Center, New York, USA.
  • 8 HiLIFE-Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.
PMID: 36912192 DOI: 10.1242/dmm.049692
Abstract

Growth factors secreted by stromal fibroblasts regulate the intestinal epithelium. Stroma-derived Epidermal growth factor (EGF) family ligands are implicated in epithelial regeneration and tumorigenesis, but their specific contributions and associated mechanisms remain unclear. Here, we use primary intestinal organoids modeling homeostatic, injured, and tumorigenic epithelium to assess how fibroblast-derived EGF family ligands Neuregulin-1 (NRG1) and Epiregulin (EREG) regulate the intestinal epithelium. NRG1 was expressed exclusively in the stroma, robustly increased crypt budding and protected intestinal epithelial organoids from radiation-induced damage. NRG1 also induced regenerative features in the epithelium including a fetal-like transcriptome, suppression of the Lgr5+ stem cell pool, and remodeling of the epithelial actin Cytoskeleton. Intriguingly, unlike EGF and EREG, NRG1 failed to support the growth of pre-tumorigenic intestinal organoids lacking the tumor suppressor APC, commonly mutated in human colorectal Cancer (CRC). Interestingly, high expression of stromal NRG1 was associated with improved survival in CRC cohorts, suggesting a tumor suppressive function. Our results highlight the power of stromal NRG1 in transcriptional reprogramming and protection of the intestinal epithelium from radiation injury without promoting tumorigenesis.

Keywords

Colorectal cancer; EGF; EREG; Intestinal regeneration; NRG1.

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