Paracrine orchestration of intestinal tumorigenesis by a mesenchymal niche

Manolis Roulis (), Aimilios Kaklamanos, Marina Schernthanner, Piotr Bielecki, Jun Zhao, Eleanna Kaffe, Laura-Sophie Frommelt, Rihao Qu, Marlene S. Knapp, Ana Henriques, Niki Chalkidi, Vasiliki Koliaraki, Jing Jiao, J. Richard Brewer, Maren Bacher, Holly N. Blackburn, Xiaoyun Zhao, Richard M. Breyer, Vassilis Aidinis, Dhanpat Jain, Bing Su, Harvey R. Herschman, Yuval Kluger, George Kollias () and Richard A. Flavell ()
Additional contact information
Manolis Roulis: Yale University School of Medicine
Aimilios Kaklamanos: Biomedical Sciences Research Center ‘Alexander Fleming’
Marina Schernthanner: Yale University School of Medicine
Piotr Bielecki: Yale University School of Medicine
Jun Zhao: Yale University School of Medicine
Eleanna Kaffe: Yale University School of Medicine
Laura-Sophie Frommelt: Yale University School of Medicine
Rihao Qu: Yale University School of Medicine
Marlene S. Knapp: Yale University School of Medicine
Ana Henriques: Biomedical Sciences Research Center ‘Alexander Fleming’
Niki Chalkidi: Biomedical Sciences Research Center ‘Alexander Fleming’
Vasiliki Koliaraki: Biomedical Sciences Research Center ‘Alexander Fleming’
Jing Jiao: David Geffen School of Medicine, UCLA
J. Richard Brewer: Yale University School of Medicine
Maren Bacher: Yale University School of Medicine
Holly N. Blackburn: Yale University School of Medicine
Xiaoyun Zhao: Shanghai Jiao Tong University School of Medicine
Richard M. Breyer: Tennessee Valley Health Authority
Vassilis Aidinis: Biomedical Sciences Research Center ‘Alexander Fleming’
Dhanpat Jain: Yale University School of Medicine
Bing Su: Shanghai Jiao Tong University School of Medicine
Harvey R. Herschman: David Geffen School of Medicine, UCLA
Yuval Kluger: Yale University
George Kollias: Biomedical Sciences Research Center ‘Alexander Fleming’
Richard A. Flavell: Yale University School of Medicine

Nature, 2020, vol. 580, issue 7804, 524-529

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41586-020-2166-3

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