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Original article
STAT3 activation through IL-6/IL-11 in cancer-associated fibroblasts promotes colorectal tumour development and correlates with poor prognosis
  1. Christina Heichler1,
  2. Kristina Scheibe1,
  3. Anabel Schmied1,
  4. Carol I Geppert2,
  5. Benjamin Schmid3,
  6. Stefan Wirtz1,
  7. Oana-Maria Thoma1,4,
  8. Viktoria Kramer1,
  9. Maximilian J Waldner1,
  10. Christian Büttner5,
  11. Henner F Farin6,7,
  12. Marina Pešić7,
  13. Ferdinand Knieling1,8,
  14. Susanne Merkel9,
  15. Anika Grüneboom10,
  16. Matthias Gunzer11,
  17. Robert Grützmann9,
  18. Stefan Rose-John12,
  19. Sergei B Koralov13,
  20. George Kollias14,
  21. Michael Vieth15,
  22. Arndt Hartmann2,
  23. Florian R Greten7,
  24. Markus F Neurath1,
  25. Clemens Neufert1
  1. 1 First Department of Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
  2. 2 Department of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
  3. 3 Optical Imaging Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
  4. 4 Erlangen Graduate School of Advanced Optical Technologies (SAOT), Friedrich Alexander University Erlangen-Nürnberg, Erlangen, Germany
  5. 5 Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
  6. 6 German Cancer Consortium (DKTK), Heidelberg, Germany
  7. 7 Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt am Main, Germany
  8. 8 Department of Pediatrics and Adolescent Medicine, Universitätsklinikum Erlangen Kinder- und Jugendklinik, Erlangen, Germany
  9. 9 Chirurgische Klinik, Universitätsklinikum Erlangen, Erlangen, Germany
  10. 10 Third Department of Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
  11. 11 Institute of Experimental Immunology and Imaging, University Duisburg-Essen and University Hospital Essen, Essen, Germany
  12. 12 Institute of Biochemistry, University of Kiel, Kiel, Germany
  13. 13 Department of Pathology, New York University School of Medicine, New York, New York, USA
  14. 14 Biomedical Sciences Research Center Alexander Fleming, Vari, Greece
  15. 15 Institute of Pathology, Klinikum Bayreuth, Bayreuth, Germany
  1. Correspondence to Dr Clemens Neufert, First Department of Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany; Clemens.Neufert{at}uk-erlangen.de

Abstract

Objective Cancer-associated fibroblasts (CAFs) influence the tumour microenvironment and tumour growth. However, the role of CAFs in colorectal cancer (CRC) development is incompletely understood.

Design We quantified phosphorylation of STAT3 (pSTAT3) expression in CAFs of human colon cancer tissue using a tissue microarray (TMA) of 375 patients, immunofluorescence staining and digital pathology. To investigate the functional role of CAFs in CRC, we took advantage of two murine models of colorectal neoplasia and advanced imaging technologies. In loss-of-function and gain-of-function experiments, using genetically modified mice with collagen type VI (COLVI)-specific signal transducer and activator of transcription 3 (STAT3) targeting, we evaluated STAT3 signalling in fibroblasts during colorectal tumour development. We performed a comparative gene expression profiling by whole genome RNA-sequencing of fibroblast subpopulations (COLVI+ vs COLVI–) on STAT3 activation (IL-6 vs IL-11).

Results The analysis of pSTAT3 expression in CAFs of human TMAs revealed a negative correlation of increased stromal pSTAT3 expression with the survival of colon cancer patients. In the loss-of-function and gain-of-function approach, we found a critical role of STAT3 activation in fibroblasts in driving colorectal tumourigenesis in vivo. With different imaging technologies, we detected an expansion of activated fibroblasts in colorectal neoplasias. Comparative gene expression profiling of fibroblast subpopulations on STAT3 activation revealed the regulation of transcriptional patterns associated with angiogenesis. Finally, the blockade of proangiogenic signalling significantly reduced colorectal tumour growth in mice with constitutive STAT3 activation in COLVI+ fibroblasts.

Conclusion Altogether our work demonstrates a critical role of STAT3 activation in CAFs in CRC development.

  • colorectal cancer
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Footnotes

  • Twitter @FerdiKnie

  • Correction notice This article has been corrected since it published Online First. The author names and affiliations have been updated.

  • Contributors CH, KS, AS, CIG, BS, SW, O-MT, VK, MJW, HF, SM, AG, MG, RG, SR-J, SK, GK, MV, AH, FG and CN provided reagents, protocols, samples or designed experiments. MP generated the genetically engineered APTAK organoids. CB analysed RNA-sequencing data. CH, KS, O-MT, VK and FK performed experiments. CH, MFN and CN analysed, discussed and interpreted data. CH, MFN and CN wrote the manuscript.

  • Funding This study was funded by the DFG (FOR2438 to CN and MFN, NE1927/2-2 to CN, SFB1181-C02 to CN and TRR241-A08 to CN), by the Interdisciplinary Centre for Clinical Research Erlangen (to CN), by the FAU Emerging Fields Initiative (to CN) and by the Rudolf Bartling Stiftung (to CN).

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.

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