BRAF V600E -mutated serrated colorectal neoplasia drives transcriptional activation of cholesterol metabolism
Abstract BRAF mutations occur early in serrated colorectal cancers, but their long-term influence on tissue homeostasis is poorly characterized. We investigated the impact of short-term (3 days) and long-term (6 months) expression of Braf V600E in the intestinal tissue of an inducible mouse model. W...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-09-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-023-05331-x |
| _version_ | 1797557206006104064 |
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| author | Paulina Rzasa Sarah Whelan Pooyeh Farahmand Hong Cai Inna Guterman Raquel Palacios-Gallego Shanthi S. Undru Lauren Sandford Caleb Green Catherine Andreadi Maria Mintseva Emma Parrott Hong Jin Fiona Hey Susan Giblett Nicolas B. Sylvius Natalie S. Allcock Anna Straatman-Iwanowska Roberto Feuda Cristina Tufarelli Karen Brown Catrin Pritchard Alessandro Rufini |
| author_facet | Paulina Rzasa Sarah Whelan Pooyeh Farahmand Hong Cai Inna Guterman Raquel Palacios-Gallego Shanthi S. Undru Lauren Sandford Caleb Green Catherine Andreadi Maria Mintseva Emma Parrott Hong Jin Fiona Hey Susan Giblett Nicolas B. Sylvius Natalie S. Allcock Anna Straatman-Iwanowska Roberto Feuda Cristina Tufarelli Karen Brown Catrin Pritchard Alessandro Rufini |
| author_sort | Paulina Rzasa |
| collection | DOAJ |
| description | Abstract BRAF mutations occur early in serrated colorectal cancers, but their long-term influence on tissue homeostasis is poorly characterized. We investigated the impact of short-term (3 days) and long-term (6 months) expression of Braf V600E in the intestinal tissue of an inducible mouse model. We show that Braf V600E perturbs the homeostasis of intestinal epithelial cells, with impaired differentiation of enterocytes emerging after prolonged expression of the oncogene. Moreover, Braf V600E leads to a persistent transcriptional reprogramming with enrichment of numerous gene signatures indicative of proliferation and tumorigenesis, and signatures suggestive of metabolic rewiring. We focused on the top-ranking cholesterol biosynthesis signature and confirmed its increased expression in human serrated lesions. Functionally, the cholesterol lowering drug atorvastatin prevents the establishment of intestinal crypt hyperplasia in Braf V600E -mutant mice. Overall, our work unveils the long-term impact of Braf V600E expression in intestinal tissue and suggests that colorectal cancers with mutations in BRAF might be prevented by statins. |
| first_indexed | 2024-03-10T17:14:04Z |
| format | Article |
| id | doaj.art-5828d5c89bd847229a7981584ed826a9 |
| institution | Directory Open Access Journal |
| issn | 2399-3642 |
| language | English |
| last_indexed | 2024-03-10T17:14:04Z |
| publishDate | 2023-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj.art-5828d5c89bd847229a7981584ed826a92023-11-20T10:33:17ZengNature PortfolioCommunications Biology2399-36422023-09-016111610.1038/s42003-023-05331-xBRAF V600E -mutated serrated colorectal neoplasia drives transcriptional activation of cholesterol metabolismPaulina Rzasa0Sarah Whelan1Pooyeh Farahmand2Hong Cai3Inna Guterman4Raquel Palacios-Gallego5Shanthi S. Undru6Lauren Sandford7Caleb Green8Catherine Andreadi9Maria Mintseva10Emma Parrott11Hong Jin12Fiona Hey13Susan Giblett14Nicolas B. Sylvius15Natalie S. Allcock16Anna Straatman-Iwanowska17Roberto Feuda18Cristina Tufarelli19Karen Brown20Catrin Pritchard21Alessandro Rufini22Leicester Cancer Research Centre, University of LeicesterLeicester Cancer Research Centre, University of LeicesterLeicester Cancer Research Centre, University of LeicesterLeicester Cancer Research Centre, University of LeicesterLeicester Cancer Research Centre, University of LeicesterLeicester Cancer Research Centre, University of LeicesterLeicester Cancer Research Centre, University of LeicesterLeicester Cancer Research Centre, University of LeicesterLeicester Cancer Research Centre, University of LeicesterLeicester Cancer Research Centre, University of LeicesterLeicester Cancer Research Centre, University of LeicesterLeicester Cancer Research Centre, University of LeicesterLeicester Cancer Research Centre, University of LeicesterLeicester Cancer Research Centre, University of LeicesterLeicester Cancer Research Centre, University of LeicesterNUCLEUS Genomics, Core Biotechnology Services, University of LeicesterUniversity of Leicester Core Biotechnology Services Electron Microscopy FacilityUniversity of Leicester Core Biotechnology Services Electron Microscopy FacilityDepartment of Genetics and Genome Biology, University of LeicesterLeicester Cancer Research Centre, University of LeicesterLeicester Cancer Research Centre, University of LeicesterLeicester Cancer Research Centre, University of LeicesterLeicester Cancer Research Centre, University of LeicesterAbstract BRAF mutations occur early in serrated colorectal cancers, but their long-term influence on tissue homeostasis is poorly characterized. We investigated the impact of short-term (3 days) and long-term (6 months) expression of Braf V600E in the intestinal tissue of an inducible mouse model. We show that Braf V600E perturbs the homeostasis of intestinal epithelial cells, with impaired differentiation of enterocytes emerging after prolonged expression of the oncogene. Moreover, Braf V600E leads to a persistent transcriptional reprogramming with enrichment of numerous gene signatures indicative of proliferation and tumorigenesis, and signatures suggestive of metabolic rewiring. We focused on the top-ranking cholesterol biosynthesis signature and confirmed its increased expression in human serrated lesions. Functionally, the cholesterol lowering drug atorvastatin prevents the establishment of intestinal crypt hyperplasia in Braf V600E -mutant mice. Overall, our work unveils the long-term impact of Braf V600E expression in intestinal tissue and suggests that colorectal cancers with mutations in BRAF might be prevented by statins.https://doi.org/10.1038/s42003-023-05331-x |
| spellingShingle | Paulina Rzasa Sarah Whelan Pooyeh Farahmand Hong Cai Inna Guterman Raquel Palacios-Gallego Shanthi S. Undru Lauren Sandford Caleb Green Catherine Andreadi Maria Mintseva Emma Parrott Hong Jin Fiona Hey Susan Giblett Nicolas B. Sylvius Natalie S. Allcock Anna Straatman-Iwanowska Roberto Feuda Cristina Tufarelli Karen Brown Catrin Pritchard Alessandro Rufini BRAF V600E -mutated serrated colorectal neoplasia drives transcriptional activation of cholesterol metabolism Communications Biology |
| title | BRAF V600E -mutated serrated colorectal neoplasia drives transcriptional activation of cholesterol metabolism |
| title_full | BRAF V600E -mutated serrated colorectal neoplasia drives transcriptional activation of cholesterol metabolism |
| title_fullStr | BRAF V600E -mutated serrated colorectal neoplasia drives transcriptional activation of cholesterol metabolism |
| title_full_unstemmed | BRAF V600E -mutated serrated colorectal neoplasia drives transcriptional activation of cholesterol metabolism |
| title_short | BRAF V600E -mutated serrated colorectal neoplasia drives transcriptional activation of cholesterol metabolism |
| title_sort | braf v600e mutated serrated colorectal neoplasia drives transcriptional activation of cholesterol metabolism |
| url | https://doi.org/10.1038/s42003-023-05331-x |
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