Paracrine orchestration of intestinal tumorigenesis by a mesenchymal niche
| العنوان: | Paracrine orchestration of intestinal tumorigenesis by a mesenchymal niche |
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| المؤلفون: | Bing Su, Piotr Bielecki, George Kollias, Vassilis Aidinis, Richard M. Breyer, J Richard Brewer, Ana Henriques, Maren Bacher, Rihao Qu, Manolis Roulis, Jing Jiao, Niki Chalkidi, Dhanpat Jain, Harvey R. Herschman, Eleanna Kaffe, Xiaoyun Zhao, Aimilios Kaklamanos, Marlene S Knapp, Holly N. Blackburn, Jun Zhao, Marina Schernthanner, Richard A. Flavell, Laura-Sophie Frommelt, Vasiliki Koliaraki, Yuval Kluger |
| المصدر: | Nature. 580:524-529 |
| بيانات النشر: | Springer Science and Business Media LLC, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, education.field_of_study, Hippo signaling pathway, Multidisciplinary, Mesenchyme, Population, Mesenchymal stem cell, Paracrine Communication, Biology, Cell biology, 03 medical and health sciences, Paracrine signalling, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, 030220 oncology & carcinogenesis, medicine, Stem cell, education, Reprogramming |
| الوصف: | 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. |
| تدمد: | 1476-4687 0028-0836 |
| DOI: | 10.1038/s41586-020-2166-3 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::0fdf8785d74b39637b0f97de920fc2f4 https://doi.org/10.1038/s41586-020-2166-3 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi...........0fdf8785d74b39637b0f97de920fc2f4 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14764687 00280836 |
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| DOI: | 10.1038/s41586-020-2166-3 |