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dc.contributor.authorLionarons, DAen_US
dc.contributor.authorHancock, DCen_US
dc.contributor.authorRana, Sen_US
dc.contributor.authorEast, Pen_US
dc.contributor.authorMoore, Cen_US
dc.contributor.authorMurillo, MMen_US
dc.contributor.authorCarvalho, Jen_US
dc.contributor.authorSpencer-Dene, Ben_US
dc.contributor.authorHerbert, Een_US
dc.contributor.authorStamp, Gen_US
dc.contributor.authorDamry, Den_US
dc.contributor.authorCalado, DPen_US
dc.contributor.authorRosewell, Ien_US
dc.contributor.authorFritsch, Ren_US
dc.contributor.authorNeubig, RRen_US
dc.contributor.authorMolina-Arcas, Men_US
dc.contributor.authorDownward, Jen_US
dc.date.accessioned2020-06-03T11:42:32Z
dc.date.issued2019-07
dc.identifier.citationCancer cell, 2019, 36 (1), pp. 68 - 83.e9
dc.identifier.issn1535-6108
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3689
dc.identifier.eissn1878-3686
dc.identifier.doi10.1016/j.ccell.2019.05.015
dc.description.abstractRAC1 P29 is the third most commonly mutated codon in human cutaneous melanoma, after BRAF V600 and NRAS Q61. Here, we study the role of RAC1P29S in melanoma development and reveal that RAC1P29S activates PAK, AKT, and a gene expression program initiated by the SRF/MRTF transcriptional pathway, which results in a melanocytic to mesenchymal phenotypic switch. Mice with ubiquitous expression of RAC1P29S from the endogenous locus develop lymphoma. When expressed only in melanocytes, RAC1P29S cooperates with oncogenic BRAF or with NF1-loss to promote tumorigenesis. RAC1P29S also drives resistance to BRAF inhibitors, which is reversed by SRF/MRTF inhibitors. These findings establish RAC1P29S as a promoter of melanoma initiation and mediator of therapy resistance, while identifying SRF/MRTF as a potential therapeutic target.
dc.formatPrint-Electronic
dc.format.extent68 - 83.e9
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectCell Line, Tumor
dc.subjectMelanocytes
dc.subjectAnimals
dc.subjectMice, Transgenic
dc.subjectHumans
dc.subjectMice
dc.subjectMelanoma
dc.subjectCell Transformation, Neoplastic
dc.subjectDisease Models, Animal
dc.subjectrac1 GTP-Binding Protein
dc.subjectProto-Oncogene Proteins B-raf
dc.subjectSerum Response Factor
dc.subjectProtein Kinase Inhibitors
dc.subjectPrognosis
dc.subjectXenograft Model Antitumor Assays
dc.subjectAmino Acid Substitution
dc.subjectCell Survival
dc.subjectGene Expression
dc.subjectDrug Resistance, Neoplasm
dc.subjectMutation
dc.subjectAlleles
dc.subjectModels, Biological
dc.subjectFemale
dc.subjectMale
dc.subjectEpithelial-Mesenchymal Transition
dc.titleRAC1P29S Induces a Mesenchymal Phenotypic Switch via Serum Response Factor to Promote Melanoma Development and Therapy Resistance.
dc.typeJournal Article
dcterms.dateAccepted2019-05-24
rioxxterms.versionofrecord10.1016/j.ccell.2019.05.015
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2019-07
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfCancer cell
pubs.issue1
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Lung Cancer Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams/Experimental Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Lung Cancer Group
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.publication-statusPublished
pubs.volume36
pubs.embargo.termsNot known
icr.researchteamExperimental Pathologyen_US
icr.researchteamLung Cancer Groupen_US
dc.contributor.icrauthorStamp, Gordonen
dc.contributor.icrauthorDownward, Julian David Harryen


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