{"doi":"10.1053/j.gastro.2020.09.011","title":"Expression of R-Spondin 1 in Apc Mice Suppresses Growth of Intestinal Adenomas by Altering Wnt and Transforming Growth Factor Beta Signaling","abstract":null,"journal":"Gastroenterology","year":2021,"id":612816,"datarank":0.5983476069846413,"base_score":3.9889840465642745,"endowment":3.9889840465642745,"self_citation_contribution":0.5983476069846413,"citation_network_contribution":0.0,"self_endowment_contribution":0.5983476069846413,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":53,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":22,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1578085,"name":"Sarika Heino","orcid":null,"position":1,"is_corresponding":false},{"id":1046061,"name":"Jenny Högström","orcid":"0000-0001-5932-0146","position":2,"is_corresponding":false},{"id":500330,"name":"Seppo Kaijalainen","orcid":null,"position":3,"is_corresponding":false},{"id":1578090,"name":"Andrey Anisimov","orcid":"0000-0003-0259-1273","position":4,"is_corresponding":false},{"id":1578092,"name":"Dustin Flanagan","orcid":null,"position":5,"is_corresponding":false},{"id":1578094,"name":"Pauliina Kallio","orcid":"0000-0001-6374-6203","position":6,"is_corresponding":false},{"id":1578097,"name":"Veli-Matti Leppänen","orcid":null,"position":7,"is_corresponding":false},{"id":1578098,"name":"Ari Ristimäki","orcid":"0000-0002-5373-9234","position":8,"is_corresponding":false},{"id":654707,"name":"Olli Ritvos","orcid":"0000-0001-7017-6931","position":9,"is_corresponding":false},{"id":750711,"name":"Katherine Wu","orcid":"0000-0002-3159-517X","position":10,"is_corresponding":false},{"id":14824,"name":"Tuomas Tammela","orcid":"0000-0003-3675-6961","position":11,"is_corresponding":false},{"id":1578099,"name":"Michael Hodder","orcid":null,"position":12,"is_corresponding":false},{"id":65393,"name":"Owen J. Sansom","orcid":"0000-0001-9540-3010","position":13,"is_corresponding":false},{"id":191885,"name":"Kari Alitalo","orcid":null,"position":14,"is_corresponding":false},{"id":1578083,"name":"Marianne Lähde","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Expression of R-Spondin 1 in Apc Mice Suppresses Growth of Intestinal Adenomas by Altering Wnt and Transforming Growth Factor Beta Signaling","abstract":"<h4>Background & aims</h4>Mutations in the APC gene and other genes in the Wnt signaling pathway contribute to development of colorectal carcinomas. R-spondins (RSPOs) are secreted proteins that amplify Wnt signaling in intestinal stem cells. Alterations in RSPO genes have been identified in human colorectal tumors. We studied the effects of RSPO1 overexpression in Apc<sup>Min/+</sup> mutant mice.<h4>Methods</h4>An adeno associated viral vector encoding RSPO1-Fc fusion protein, or control vector, was injected into Apc<sup>Min/+</sup>mice. Their intestinal crypts were isolated and cultured as organoids. which were incubated with or without RSPO1-Fc and an inhibitor of transforming growth factor beta receptor (TGFBR). Livers were collected from mice and analyzed by immunohistochemistry. Organoids and adenomas were analyzed by quantitative reverse-transcription PCR, single cell RNA sequencing, and immunohistochemistry.<h4>Results</h4>Intestines from Apc<sup>+/+</sup> mice injected with the vector encoding RSPO1-Fc had significantly deeper crypts, longer villi, with increased EdU labeling, indicating increased proliferation of epithelial cells, in comparison to mice given control vector. AAV-RSPO1-Fc-transduced Apc<sup>Min/+</sup> mice also developed fewer and smaller intestinal tumors and had significantly longer survival times. Adenomas of Apc<sup>Min/+</sup> mice injected with the RSPO1-Fc vector showed a rapid increase in apoptosis and in the expression of Wnt target genes, followed by reduced expression of messenger RNAs and proteins regulated by the Wnt pathway, reduced cell proliferation, and less crypt branching than adenomas of mice given the control vector. Addition of RSPO1 reduced the number of adenoma organoids derived from Apc<sup>Min/+</sup> mice and suppressed expression of Wnt target genes but increased phosphorylation of SMAD2 and transcription of genes regulated by SMAD. Inhibition of TGFBR signaling in organoids stimulated with RSPO1-Fc restored organoid formation and expression of genes regulated by Wnt. The TGFBR inhibitor restored apoptosis in adenomas from Apc<sup>Min/+</sup> mice expressing RSPO1-Fc back to the same level as in the adenomas from mice given the control vector.<h4>Conclusions</h4>Expression of RSPO1 in Apc<sup>Min/+</sup> mice increases apoptosis and reduces proliferation and Wnt signaling in adenoma cells, resulting in development of fewer and smaller intestinal tumors and longer mouse survival. Addition of RSPO1 to organoids derived from adenomas inhibits their growth and promotes proliferation of intestinal stem cells that retain the APC protein; these effects are reversed by TGFB inhibitor. Strategies to increase the expression of RSPO1 might be developed for the treatment of intestinal adenomas.","is_dataset_classified":null,"base_score":3.9889840465642745,"endowment":3.9889840465642745,"datacite_reuse_total":22,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"32941878","pmcid":null,"openalex_id":"https://openalex.org/W3086247943","authors":[],"funders":[{"funder_name":"National Cancer Institute","grant_id":"R00CA187317","title":null},{"funder_name":"American Association for Cancer Research","grant_id":"18-20-01-TAMM","title":null},{"funder_name":"Cancer Research UK","grant_id":"A17196","title":null},{"funder_name":"Academy of Finland","grant_id":"2019-2022","title":null},{"funder_name":"Academy of Finland","grant_id":"273817","title":null},{"funder_name":"Academy of Finland","grant_id":"320185","title":"iCAN – The Digital Precision Cancer Medicine Platform"},{"funder_name":"Cancer Foundation Finland sr","grant_id":"190100","title":null},{"funder_name":"Cancer Research UK","grant_id":"21139","title":null},{"funder_name":"National Institutes of Health","grant_id":"4R00CA187317-03","title":"Investigating cellular heterogeneity in lung cancer"},{"funder_name":"Research Council of Finland","grant_id":"307366","title":"Centre of Excellence in Translational Cancer Biology"},{"funder_name":"Biocenter Finland","grant_id":"","title":null},{"funder_name":"Helsingin Yliopisto","grant_id":"","title":null},{"funder_name":"Syöpäsäätiö","grant_id":"","title":null},{"funder_name":"Biomedicum Helsinki-säätiö","grant_id":"","title":null},{"funder_name":"Sigrid Juséliuksen Säätiö","grant_id":"","title":null},{"funder_name":"Suomen Lääketieteen Säätiö","grant_id":"","title":null},{"funder_name":"Helsinki Institute of Life Science, Helsingin Yliopisto","grant_id":"","title":null}],"total_grants":17,"fwci":1.9751,"citation_percentile":0.89001438,"influential_citations":0,"citation_trend":[{"year":2020,"count":1},{"year":2021,"count":2},{"year":2022,"count":8},{"year":2023,"count":15},{"year":2024,"count":17},{"year":2025,"count":8},{"year":2026,"count":2}],"oa_status":"green","license":"cc-by-sa","oa_locations":[{"url":"https://api.elsevier.com/content/article/PII:S0016508520351489?httpAccept=text/xml","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S0016508520351489?httpAccept=text/plain","host_type":"publisher"},{"url":"https://doi.org/10.1053/j.gastro.2020.09.011","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/32941878","host_type":"repository"},{"url":"http://hdl.handle.net/10138/334329","host_type":"journal"},{"url":"http://eprints.gla.ac.uk/227929/3/227929.pdf","host_type":""},{"url":"https://eprints.gla.ac.uk/227929/3/227929.pdf","host_type":""},{"url":"https://dx.doi.org/10.1053/j.gastro.2020.09.011","host_type":""}],"fields_of_study":["Cancer Cells and Metastasis","Wnt/β-catenin signaling in development and cancer","Liver physiology and pathology","0301 basic medicine","0303 health sciences","03 medical and health sciences","Adenoma","Animals","Disease Models, Animal","Intestinal Neoplasms","Mice","Organoids","Thrombospondins","Transforming Growth Factor beta","Wnt Signaling Pathway"],"mesh_terms":["Adenoma","Animals","Disease Models, Animal","Intestinal Neoplasms","Organoids","Transforming Growth Factor beta","Thrombospondins","Mice","Wnt Signaling Pathway"],"keywords":["Wnt signaling pathway","Biology","LGR5","Organoid","Cancer research","Beta-catenin","Molecular biology","Cell growth","Stem cell","Transforming growth factor beta","Cell biology","Signal transduction","Genetics","Colon cancer","Familial Adenomatous Polyposis","Prox1","Adenoma","Organoids","Disease Models, Animal","Mice","Intestinal Neoplasms","Animals","Thrombospondins"],"sdg_mappings":[{"sdg_number":2,"sdg_label":"2. 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