Secreted Phospholipases A2 Are Intestinal Stem Cell Niche Factors with Distinct Roles in Homeostasis, Inflammation, and Cancer.
The intestinal stem cell niche provides cues that actively maintain gut homeostasis. Dysregulation of these cues may compromise intestinal regeneration upon tissue insult and/or promote tumor growth. Here, we identify secreted phospholipases A2 (sPLA2s) as stem cell niche factors with context-dependent functions in the digestive tract. We show that group IIA sPLA2, a known genetic modifier of mouse intestinal tumorigenesis, is expressed by Paneth cells in the small intestine, while group X sPLA2 is expressed by Paneth/goblet-like cells in the colon. During homeostasis, group IIA/X sPLA2s inhibit Wnt signaling through intracellular activation of Yap1. However, upon inflammation they are secreted into the intestinal lumen, where they promote prostaglandin synthesis and Wnt signaling. Genetic ablation of both sPLA2s improves recovery from inflammation but increases colon cancer susceptibility due to release of their homeostatic Wnt-inhibitory role. This "trade-off" effect suggests sPLA2s have important functions as genetic modifiers of inflammation and colon cancer.
Department of Pathology, Erasmus MC Cancer Institute, Rotterdam 3000CA, The Netherlands.
Matthias
M
Schewe
Department of Pathology, Erasmus MC Cancer Institute, Rotterdam 3000CA, The Netherlands.
Patrick F
PF
Franken
Department of Pathology, Erasmus MC Cancer Institute, Rotterdam 3000CA, The Netherlands.
Andrea
A
Sacchetti
Department of Pathology, Erasmus MC Cancer Institute, Rotterdam 3000CA, The Netherlands.
Mark
M
Schmitt
Department of Pathology, Erasmus MC Cancer Institute, Rotterdam 3000CA, The Netherlands.
Rosalie
R
Joosten
Department of Urology, Erasmus MC Cancer Institute, Rotterdam 3000CA, The Netherlands.
René
R
Böttcher
Department of Pathology, Erasmus MC Cancer Institute, Rotterdam 3000CA, The Netherlands; Erasmus Optical Imaging Centre, Erasmus MC Cancer Institute, Rotterdam 3000CA, The Netherlands.
Martin E
ME
van Royen
Institute of Molecular and Cellular Pharmacology, Centre National de la Recherche Scientifique and University of Nice Sophia Antipolis, Valbonne 06560, France.
Louise
L
Jeammet
Institute of Molecular and Cellular Pharmacology, Centre National de la Recherche Scientifique and University of Nice Sophia Antipolis, Valbonne 06560, France.
Christine
C
Payré
Department of Biomedical Sciences, University of Minnesota Medical School Duluth, Duluth, MN 55812-3031, USA.
Patricia M
PM
Scott
Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40506-9983, USA.
Nancy R
NR
Webb
Department of Chemistry, University of Washington, Seattle, WA 98195-1700, USA.
Michael
M
Gelb
Department of Biomedical Sciences, University of Minnesota Medical School Duluth, Duluth, MN 55812-3031, USA.
Robert T
RT
Cormier
Institute of Molecular and Cellular Pharmacology, Centre National de la Recherche Scientifique and University of Nice Sophia Antipolis, Valbonne 06560, France.
Gérard
G
Lambeau
Department of Pathology, Erasmus MC Cancer Institute, Rotterdam 3000CA, The Netherlands. Electronic address: r.fodde@erasmusmc.nl.
Riccardo
R
Fodde
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D019070:Cell Lineage; D015232:Dinoprostone / Q000096:biosynthesis; D054501:Group II Phospholipases A2 / Q000378:metabolism*; D054509:Group X Phospholipases A2 / Q000378:metabolism*; D006706:Homeostasis; D007249:Inflammation / Q000201:enzymology / Q000473:pathology*; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000473:pathology; D007414:Intestinal Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D007422:Intestines / Q000473:pathology*; D042541:Intracellular Space / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009940:Organoids / Q000378:metabolism; D019879:Paneth Cells / Q000201:enzymology / Q000473:pathology; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D055153:Stem Cell Niche; D013234:Stem Cells / Q000473:pathology; D060449:Wnt Signaling Pathway; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D054501:Group II Phospholipases A2; D054509:Group X Phospholipases A2; C516366:Pla2g10 protein, mouse; C516288:Pla2g2a protein, mouse; D015232:Dinoprostone