Secreted Phospholipases A2 Are Intestinal Stem Cell Niche Factors with Distinct Roles in Homeostasis, Inflammation, and Cancer

• Published in: Cell stem cell 2016-07, Vol.19 (1), p.38-51
• Main Authors: Schewe, Matthias, Franken, Patrick F., Sacchetti, Andrea, Schmitt, Mark, Joosten, Rosalie, Böttcher, René, van Royen, Martin E., Jeammet, Louise, Payré, Christine, Scott, Patricia M., Webb, Nancy R., Gelb, Michael, Cormier, Robert T., Lambeau, Gérard, Fodde, Riccardo
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Animals; Cell Cycle Proteins; Cell Differentiation; Cell Lineage; Dinoprostone - biosynthesis; Group II Phospholipases A2 - metabolism; Group X Phospholipases A2 - metabolism; Homeostasis; Inflammation - enzymology; Inflammation - pathology; Inflammatory Bowel Diseases - genetics; Inflammatory Bowel Diseases - pathology; Intestinal Neoplasms - enzymology; Intestinal Neoplasms - genetics; Intestinal Neoplasms - pathology; Intestines - pathology; Intracellular Space - metabolism; Mice, Inbred C57BL; Organoids - metabolism; Paneth Cells - enzymology; Paneth Cells - pathology; Phosphoproteins - metabolism; Phosphorylation; Stem Cell Niche; Stem Cells - pathology; Wnt Signaling Pathway
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2016.05.023

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. [Display omitted] •Intracellular group IIA and X phospholipases A2 restrict Wnt signaling through Yap1•During inflammation, the same phospholipases are secreted and promote Wnt signaling•Group X phospholipase A2 is expressed in Paneth-like cells in the colon•Genetic ablation of both group IIA and X predisposes mice to colon cancer Pla2g2a, encoding group IIA secreted phospholipase A2, is an important genetic modifier of intestinal tumorigenesis. Schewe et al. report group IIA/X secreted phospholipases A2 are intestinal stem cell niche factors with cell-intrinsic and secreted functions in Wnt signaling and prostaglandin synthesis that modulate intestinal homeostasis, inflammation, and cancer susceptibility.