TY - JOUR
TI - Paracrine orchestration of intestinal tumorigenesis by a mesenchymal niche
AU - Roulis, M.
AU - Kaklamanos, A.
AU - Schernthanner, M.
AU - Bielecki, P.
AU - Zhao, J.
AU - Kaffe, E.
AU - Frommelt, L.-S.
AU - Qu, R.
AU - Knapp, M.S.
AU - Henriques, A.
AU - Chalkidi, N.
AU - Koliaraki, V.
AU - Jiao, J.
AU - Brewer, J.R.
AU - Bacher, M.
AU - Blackburn, H.N.
AU - Zhao, X.
AU - Breyer, R.M.
AU - Aidinis, V.
AU - Jain, D.
AU - Su, B.
AU - Herschman, H.R.
AU - Kluger, Y.
AU - Kollias, G.
AU - Flavell, R.A.
JO - Nature
PY - 2020
VL - 580
TODO - 7804
SP - 524-529
PB - Institute of Geographic Sciences and Natural Resources Research
SN - 0028-0836
TODO - 10.1038/s41586-020-2166-3
TODO - arachidonic acid;  prostaglandin E receptor 4;  prostaglandin E2;  transcription factor Yap1;  arachidonic acid;  cell cycle protein;  cyclooxygenase 2;  Ly antigen;  Ly6a protein, mouse;  membrane protein;  prostaglandin E receptor 4;  prostaglandin E2;  PTGER4 protein, human;  Ptger4 protein, mouse;  signal transducing adaptor protein;  Yap protein, mouse, ablation;  cancer;  cell;  heterogeneity;  mutation;  rodent;  translocation;  tumor, adenoma;  animal cell;  animal experiment;  animal model;  animal tissue;  Article;  carcinogenesis;  cell expansion;  cell function;  cell population;  controlled study;  evidence based medicine;  fibroblast;  gene expression;  human;  human cell;  human tissue;  in vivo study;  mesenchymal stem cell;  mouse;  nonhuman;  organoid;  paracrine signaling;  priority journal;  protein dephosphorylation;  RNA sequencing;  sequence analysis;  signal transduction;  stem cell niche;  animal;  cancer stem cell;  cell proliferation;  colorectal tumor;  female;  intestine;  intestine mucosa;  male;  mesoderm;  metabolism;  pathology;  single cell analysis, Mus, Adaptor Proteins, Signal Transducing;  Animals;  Antigens, Ly;  Arachidonic Acid;  Carcinogenesis;  Cell Cycle Proteins;  Cell Proliferation;  Colorectal Neoplasms;  Cyclooxygenase 2;  Dinoprostone;  Female;  Fibroblasts;  Humans;  Intestinal Mucosa;  Intestines;  Male;  Membrane Proteins;  Mesoderm;  Mice;  Neoplastic Stem Cells;  Organoids;  Paracrine Communication;  Receptors, Prostaglandin E, EP4 Subtype;  Single-Cell Analysis;  Stem Cell Niche
TODO - The initiation of an intestinal tumour is a probabilistic process that depends on the competition between mutant and normal epithelial stem cells in crypts1. Intestinal stem cells are closely associated with a diverse but poorly characterized network of mesenchymal cell types2,3. However, whether the physiological mesenchymal microenvironment of mutant stem cells affects tumour initiation remains unknown. Here we provide in vivo evidence that the mesenchymal niche controls tumour initiation in trans. By characterizing the heterogeneity of the intestinal mesenchyme using single-cell RNA-sequencing analysis, we identified a population of rare pericryptal Ptgs2-expressing fibroblasts that constitutively process arachidonic acid into highly labile prostaglandin E2 (PGE2). Specific ablation of Ptgs2 in fibroblasts was sufficient to prevent tumour initiation in two different models of sporadic, autochthonous tumorigenesis. Mechanistically, single-cell RNA-sequencing analyses of a mesenchymal niche model showed that fibroblast-derived PGE2 drives the expansion οf a population of Sca-1+ reserve-like stem cells. These express a strong regenerative/tumorigenic program, driven by the Hippo pathway effector Yap. In vivo, Yap is indispensable for Sca-1+ cell expansion and early tumour initiation and displays a nuclear localization in both mouse and human adenomas. Using organoid experiments, we identified a molecular mechanism whereby PGE2 promotes Yap dephosphorylation, nuclear translocation and transcriptional activity by signalling through the receptor Ptger4. Epithelial-specific ablation of Ptger4 misdirected the regenerative reprogramming of stem cells and prevented Sca-1+ cell expansion and sporadic tumour initiation in mutant mice, thereby demonstrating the robust paracrine control of tumour-initiating stem cells by PGE2–Ptger4. Analyses of patient-derived organoids established that PGE2–PTGER4 also regulates stem-cell function in humans. Our study demonstrates that initiation of colorectal cancer is orchestrated by the mesenchymal niche and reveals a mechanism by which rare pericryptal Ptgs2-expressing fibroblasts exert paracrine control over tumour-initiating stem cells via the druggable PGE2–Ptger4–Yap signalling axis. © 2020, The Author(s), under exclusive licence to Springer Nature Limited.
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