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Loss of C3aR induces immune infiltration and inflammatory microbiota in a new spontaneous model of colon cancer

Carsten Krieg, View ORCID ProfileLukas M. Weber, Bruno Fosso, Gary Hardiman, Erika Mileti, Sahar El Aidy, Marinella Marzano, Mark D. Robinson, View ORCID ProfileSilvia Guglietta
doi: https://doi.org/10.1101/2021.01.18.426963
Carsten Krieg
1Hollings Cancer Center, Medical University of South Carolina, 29425 Charleston (SC), USA
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Lukas M. Weber
2Institute of Molecular Life Sciences, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland
3SIB Swiss Institute of Bioinformatics, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland
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Bruno Fosso
4Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, Consiglio Nazionale delle Ricerche, Bari, Italy
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Gary Hardiman
5School of Biological Sciences & Institute for Global Food Security, Queens University Belfast, BT9 5AG, Belfast, UK
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Erika Mileti
6Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy
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Sahar El Aidy
7Host-microbe metabolic interactions, Microbiology, Groningen Biomolecular Sciences and Biotechnology Institute (GBB), University of Groningen, Groningen, The Netherlands
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Marinella Marzano
4Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, Consiglio Nazionale delle Ricerche, Bari, Italy
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Mark D. Robinson
2Institute of Molecular Life Sciences, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland
3SIB Swiss Institute of Bioinformatics, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland
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Silvia Guglietta
1Hollings Cancer Center, Medical University of South Carolina, 29425 Charleston (SC), USA
6Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy
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  • ORCID record for Silvia Guglietta
  • For correspondence: gugliett@musc.edu
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ABSTRACT

Several lines of evidence suggest that inflammation plays a pivotal role in the development and progression of colorectal cancer (CRC) and can be unleashed by the loss of innate immunosurveillance. The complement system is a well characterized first line of defense against pathogens and a central component of the immune response. Emerging evidence suggests that complement anaphylatoxin C3a produced upon complement activation and acting via its receptor (C3aR) may play a role in intestinal homeostasis. However, to date, it is unknown whether and how the C3a/C3aR axis can affect CRC. By mining publicly available datasets, we found that CpG island methylation of c3ar1 occurs in CRC patients and is associated with significant downregulation of C3aR. By reverse-translating this finding we were able to shift in APCMin/+ mice the tumorigenesis from the small intestine to the colon therefore generating a novel mouse model, which more closely mirrors the CRC in humans. Transcriptomic analysis on colorectal polyps from our newly developed genetic mouse model revealed a significant increase in innate and adaptive immune signatures in absence of C3aR. Furthermore, loss of C3aR significantly impacted the fecal and tumor-associated microbiota and supported the blooming of pro-inflammatory bacterial species as confirmed by experiments of fecal microbiota transplantation.

Future studies will elucidate whether loss of C3aR can be exploited as a biomarker for sub-groups of CRC and whether the C3a/C3aR axis may be exploited for the generation of more effective therapeutic interventions.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵# Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA

  • https://www.ebi.ac.uk/arrayexpress

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted August 02, 2021.
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Loss of C3aR induces immune infiltration and inflammatory microbiota in a new spontaneous model of colon cancer
Carsten Krieg, Lukas M. Weber, Bruno Fosso, Gary Hardiman, Erika Mileti, Sahar El Aidy, Marinella Marzano, Mark D. Robinson, Silvia Guglietta
bioRxiv 2021.01.18.426963; doi: https://doi.org/10.1101/2021.01.18.426963
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Loss of C3aR induces immune infiltration and inflammatory microbiota in a new spontaneous model of colon cancer
Carsten Krieg, Lukas M. Weber, Bruno Fosso, Gary Hardiman, Erika Mileti, Sahar El Aidy, Marinella Marzano, Mark D. Robinson, Silvia Guglietta
bioRxiv 2021.01.18.426963; doi: https://doi.org/10.1101/2021.01.18.426963

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