IL-1R signaling drives enteric glia-macrophage interactions in colorectal cancer

Lies van Baarle, Veronica De Simone, Linda Schneider, Sneha Santhosh, Saeed Abdurahiman, Francesca Biscu, Reiner Schneider, Lisa Zanoletti, Renata Siqueira de Mello, Sara Verbandt, Zedong Hu, Michelle Stakenborg, Bo-Jun Ke, Nathalie Stakenborg, Raquel Salvador Laureano, Balbina García-Reyes, Jonas Henn, Marieta Toma, Maxime Vanmechelen, Guy Boeckxstaens, Frederik De Smet, Abhishek D. Garg, Sales Ibiza, Sabine Tejpar, Sven Wehner () and Gianluca Matteoli ()
Additional contact information
Lies van Baarle: Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven
Veronica De Simone: Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven
Linda Schneider: University Hospital Bonn, Medical Faculty
Sneha Santhosh: Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven
Saeed Abdurahiman: Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven
Francesca Biscu: Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven
Reiner Schneider: University Hospital Bonn, Medical Faculty
Lisa Zanoletti: Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven
Renata Siqueira de Mello: Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven
Sara Verbandt: KU Leuven
Zedong Hu: KU Leuven
Michelle Stakenborg: Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven
Bo-Jun Ke: Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven
Nathalie Stakenborg: Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven
Raquel Salvador Laureano: KU Leuven
Balbina García-Reyes: University Hospital Bonn, Medical Faculty
Jonas Henn: University Hospital Bonn, Medical Faculty
Marieta Toma: University Hospital Bonn, Medical Faculty
Maxime Vanmechelen: Laboratory for Precision Cancer Medicine, KU Leuven
Guy Boeckxstaens: Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven
Frederik De Smet: Laboratory for Precision Cancer Medicine, KU Leuven
Abhishek D. Garg: KU Leuven
Sales Ibiza: University of Antwerp
Sabine Tejpar: KU Leuven
Sven Wehner: University Hospital Bonn, Medical Faculty
Gianluca Matteoli: Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven

Nature Communications, 2024, vol. 15, issue 1, 1-22

Abstract: Abstract Enteric glia have been recently recognized as key components of the colonic tumor microenvironment indicating their potential role in colorectal cancer pathogenesis. Although enteric glia modulate immune responses in other intestinal diseases, their interaction with the colorectal cancer immune cell compartment remains unclear. Through a combination of single-cell and bulk RNA-sequencing, both in murine models and patients, here we find that enteric glia acquire an immunomodulatory phenotype by bi-directional communication with tumor-infiltrating monocytes. The latter direct a reactive enteric glial cell phenotypic and functional switch via glial IL-1R signaling. In turn, tumor glia promote monocyte differentiation towards pro-tumorigenic SPP1+ tumor-associated macrophages by IL-6 release. Enteric glia cell abundancy correlates with worse disease outcomes in preclinical models and colorectal cancer patients. Thereby, our study reveals a neuroimmune interaction between enteric glia and tumor-associated macrophages in the colorectal tumor microenvironment, providing insights into colorectal cancer pathogenesis.

Date: 2024
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DOI: 10.1038/s41467-024-50438-2

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