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Original research
Epithelial presenilin-1 drives colorectal tumour growth by controlling EGFR-COX2 signalling
  1. Reyes Gamez-Belmonte1,
  2. Mousumi Mahapatro1,
  3. Lena Erkert1,
  4. Miguel Gonzalez-Acera1,
  5. Elisabeth Naschberger2,
  6. Yuqiang Yu1,3,
  7. Mireia Tena-Garitaonaindia4,
  8. Jay V Patankar1,5,
  9. Yara Wagner1,
  10. Eva Podstawa1,
  11. Lena Schödel1,
  12. Marvin Bubeck1,
  13. Markus F Neurath1,5,
  14. Michael Stürzl2,
  15. Christoph Becker1,5
  1. 1Department of Medicine 1, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
  2. 2Division of Molecular and Experimental Surgery, Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
  3. 3Duke University Medical Center, Durham, North Carolina, USA
  4. 4Department of Biochemistry and Molecular Biology 2, University of Granada, Granada, Spain
  5. 5Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
  1. Correspondence to Professor Christoph Becker, Universitätsklinikum Erlangen, Erlangen, Germany; christoph.becker{at}uk-erlangen.de

Abstract

Objective Psen1 was previously characterised as a crucial factor in the pathogenesis of neurodegeneration in patients with Alzheimer’s disease. Little, if any, is known about its function in the gut. Here, we uncovered an unexpected functional role of Psen1 in gut epithelial cells during intestinal tumourigenesis.

Design Human colorectal cancer (CRC) and control samples were investigated for PSEN1 and proteins of theγ-secretase complex. Tumour formation was analysed in the AOM-DSS and Apcmin/+ mouse models using newly generated epithelial-specific Psen1 deficient mice. Psen1 deficient human CRC cells were studied in a xenograft tumour model. Tumour-derived organoids were analysed for growth and RNA-Seq was performed to identify Psen1-regulated pathways. Tumouroids were generated to study EGFR activation and evaluation of the influence of prostanoids.

Results PSEN1 is expressed in the intestinal epithelium and its level is increased in human CRC. Psen1-deficient mice developed only small tumours and human cancer cell lines deficient in Psen1 had a reduced tumourigenicity. Tumouroids derived from Psen1-deficient Apcmin/+ mice exhibited stunted growth and reduced cell proliferation. On a molecular level, PSEN1 potentiated tumour cell proliferation via enhanced EGFR signalling and COX-2 production. Exogenous administration of PGE2 reversed the slow growth of PSEN1 deficient tumour cells via PGE2 receptor 4 (EP4) receptor signalling.

Conclusions Psen1 drives tumour development by increasing EGFR signalling via NOTCH1 processing, and by activating the COX-2-PGE2 pathway. PSEN1 inhibition could be a useful strategy in treatment of CRC.

  • colorectal cancer
  • arachidonic and metabolism
  • colorectal adenomas

Data availability statement

Data are available in a public, open access repository. All data relevant to the study are included in the article or uploaded as online supplemental information. GEO accession number: GSE212898.

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Data availability statement

Data are available in a public, open access repository. All data relevant to the study are included in the article or uploaded as online supplemental information. GEO accession number: GSE212898.

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Footnotes

  • RG-B and MM contributed equally.

  • Contributors Study concept, design, literature search, experimentation, analysis, interpretation of data, critical revision of manuscript, manuscript drafting—RG-B, MM and CB; Experimentation and analysis—LE, MG-A, EN, YY, MT-G, JVP, YW, EP, LS, MB and MS; intellectual contributions during manuscript editing, acquisition of funds and supervision—MFN and CB. Guarantor-RG-B and CB.

  • Funding This work received funding from the DFG projects SFB1181 (C02, C05), TRR241 (A02, A03, A08, B04, C02, C04 and Z03), FOR2438 (TP05, TP02), TRR241 (A06), TRR305 (B08), STU 238/10-1 and individual grant BE3686/9. The project was further supported by the Interdisciplinary Center for Clinical Research (IZKF: J96, A76).

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

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

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.