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dc.contributor.authorDrusian, Luca
dc.contributor.authorNigro, Elisa Agnese
dc.contributor.authorMannella, Valeria
dc.contributor.authorPagliarini, Roberto
dc.contributor.authorPema, Monika
dc.contributor.authorCosta, Ana SH
dc.contributor.authorBenigni, Fabio
dc.contributor.authorLarcher, Alessandro
dc.contributor.authorChiaravalli, Marco
dc.contributor.authorGaude, Edoardo
dc.contributor.authorMontorsi, Francesco
dc.contributor.authorCapitanio, Umberto
dc.contributor.authorMusco, Giovanna
dc.contributor.authorFrezza, Christian
dc.contributor.authorBoletta, Alessandra
dc.date.accessioned2018-11-01T14:02:42Z
dc.date.available2018-11-01T14:02:42Z
dc.date.issued2018-07-31
dc.identifier.issn2211-1247
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/284498
dc.description.abstractRenal cell carcinomas (RCCs) are common cancers diagnosed in more than 350,000 people each year worldwide. Several pathways are de-regulated in RCCs, including mTORC1. However, how mTOR drives tumorigenesis in this context is unknown. The lack of faithful animal models has limited progress in understanding and targeting RCCs. Here, we generated a mouse model harboring the kidney-specific inactivation of Tsc1. These animals develop cysts that evolve into papillae, cystadenomas, and papillary carcinomas. Global profiling confirmed several metabolic derangements previously attributed to mTORC1. Notably, Tsc1 inactivation results in the accumulation of fumarate and in mTOR-dependent downregulation of the TCA cycle enzyme fumarate hydratase (FH). The re-expression of FH in cellular systems lacking Tsc1 partially rescued renal epithelial transformation. Importantly, the mTORC1-FH axis is likely conserved in human RCC specimens. We reveal a role of mTORC1 in renal tumorigenesis, which depends on the oncometabolite fumarate.
dc.format.mediumPrint
dc.languageeng
dc.publisherElsevier BV
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectCells, Cultured
dc.subjectAnimals
dc.subjectMice, Inbred C57BL
dc.subjectHumans
dc.subjectMice
dc.subjectCarcinoma, Renal Cell
dc.subjectKidney Neoplasms
dc.subjectFumarates
dc.subjectFumarate Hydratase
dc.subjectUp-Regulation
dc.subjectFemale
dc.subjectMale
dc.subjectMechanistic Target of Rapamycin Complex 1
dc.subjectTuberous Sclerosis Complex 1 Protein
dc.titlemTORC1 Upregulation Leads to Accumulation of the Oncometabolite Fumarate in a Mouse Model of Renal Cell Carcinoma.
dc.typeArticle
prism.endingPage1104.e6
prism.issueIdentifier5
prism.publicationDate2018
prism.publicationNameCell Rep
prism.startingPage1093
prism.volume24
dc.identifier.doi10.17863/CAM.31873
dcterms.dateAccepted2018-06-27
rioxxterms.versionofrecord10.1016/j.celrep.2018.06.106
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-07
dc.contributor.orcidFrezza, Christian [0000-0002-3293-7397]
dc.identifier.eissn2211-1247
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMRC (unknown)
pubs.funder-project-idMedical Research Council (MC_UU_12022/6)


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Attribution-NonCommercial-NoDerivatives 4.0 International
Except where otherwise noted, this item's licence is described as Attribution-NonCommercial-NoDerivatives 4.0 International