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

Author:

Lemmetyinen Toni T.1ORCID,Viitala Emma W.1ORCID,Wartiovaara Linnea1,Kaprio Tuomas12ORCID,Hagström Jaana134ORCID,Haglund Caj12ORCID,Katajisto Pekka567ORCID,Wang Timothy C.8ORCID,Domènech-Moreno Eva9ORCID,Ollila Saara1ORCID

Affiliation:

1. University of Helsinki 1 Translational Cancer Medicine Program , , 00014 Helsinki , Finland

2. University of Helsinki and Helsinki University Hospital 2 Department of Surgery , , 00290 Helsinki , Finland

3. University of Helsinki and Helsinki University Hospital 3 Department of Pathology , , 00290 Helsinki , Finland

4. University of Turku 4 Department of Oral Pathology and Radiology , , 20014 Turku , Finland

5. Institute of Biotechnology, HiLIFE, University of Helsinki 5 , 00014 Helsinki , Finland

6. Karolinska Institutet 6 Department of Cell and Molecular Biology , , 17177 Stockholm , Sweden

7. University of Helsinki 7 Faculty of Biological and Environmental Sciences , , 00014 Helsinki , Finland

8. Irving Cancer Research Center, Columbia University Medical Center 8 Division of Digestive and Liver Diseases, Department of Medicine , , New York, NY 10032 , USA

9. HiLIFE-Helsinki Institute of Life Science, University of Helsinki 9 , 00014 Helsinki , Finland

Abstract

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 epithelia to assess how the 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.

Funder

Academy of Finland

Sigrid Juséliuksen Säätiö

Helsingin Yliopiston Kirjasto

Publisher

The Company of Biologists

Subject

General Biochemistry, Genetics and Molecular Biology,Immunology and Microbiology (miscellaneous),Medicine (miscellaneous),Neuroscience (miscellaneous)

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