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dc.contributor.authorAdam, Ronja S.
dc.contributor.authorvan Neerven, Sanne M.
dc.contributor.authorPleguezuelos-Manzano, Cayetano
dc.contributor.authorSimmini, Salvatore
dc.contributor.authorLéveillé, Nicolas
dc.contributor.authorde Groot, Nina E.
dc.contributor.authorHolding, Andrew N.
dc.contributor.authorMarkowetz, Florian
dc.contributor.authorVermeulen, Louis
dc.date.accessioned2020-12-03T16:26:43Z
dc.date.available2020-12-03T16:26:43Z
dc.date.issued2020-12-03
dc.date.submitted2020-03-08
dc.identifier.others12935-020-01661-6
dc.identifier.other1661
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/314452
dc.description.abstractAbstract: Background: Cancer results from the accumulation of mutations leading to the acquisition of cancer promoting characteristics such as increased proliferation and resistance to cell death. In colorectal cancer, an early mutation leading to such features usually occurs in the APC or CTNNB1 genes, thereby activating Wnt signalling. However, substantial phenotypic differences between cancers originating within the same organ, such as molecular subtypes, are not fully reflected by differences in mutations. Indeed, the phenotype seems to result from a complex interplay between the cell-intrinsic features and the acquired mutations, which is difficult to disentangle when established tumours are studied. Methods: We use a 3D in vitro organoid model to study the early phase of colorectal cancer development. From three different murine intestinal locations we grow organoids. These are transformed to resemble adenomas after Wnt activation through lentiviral transduction with a stable form of β-Catenin. The gene expression before and after Wnt activation is compared within each intestinal origin and across the three locations using RNA sequencing. To validate and generalize our findings, we use gene expression data from patients. Results: In reaction to Wnt activation we observe downregulation of location specific genes and differentiation markers. A similar effect is seen in patient data, where genes with significant differential expression between the normal left and right colon are downregulated in the cancer samples. Furthermore, the signature of Wnt target genes differs between the three intestinal locations in the organoids. The location specific Wnt signatures are dominated by genes which have been lowly expressed in the tissue of origin, and are the targets of transcription factors that are activated following enhanced Wnt signalling. Conclusion: We observed that the region-specific cell identity has a substantial effect on the reaction to Wnt activation in a simple intestinal adenoma model. These findings provide a way forward in resolving the distinct biology between left- and right-sided human colon cancers with potential clinical relevance.
dc.languageen
dc.publisherBioMed Central
dc.rightsAttribution 4.0 International (CC BY 4.0)en
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en
dc.subjectPrimary Research
dc.subjectIntestinal cancer
dc.subjectWnt signalling
dc.subjectCell of origin
dc.titleIntestinal region-specific Wnt signalling profiles reveal interrelation between cell identity and oncogenic pathway activity in cancer development
dc.typeArticle
dc.date.updated2020-12-03T16:26:43Z
prism.issueIdentifier1
prism.publicationNameCancer Cell International
prism.volume20
dc.identifier.doi10.17863/CAM.61556
dcterms.dateAccepted2020-11-16
rioxxterms.versionofrecord10.1186/s12935-020-01661-6
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidVermeulen, Louis [0000-0002-6066-789X]
dc.identifier.eissn1475-2867
pubs.funder-project-idKWF Kankerbestrijding (UVA2014-7245)
pubs.funder-project-idWorldwide Cancer Research (14-1164)
pubs.funder-project-idMaag Lever Darm Stichting (MLDS-CDG 14-03)
pubs.funder-project-idH2020 European Research Council (ERG-StG 638193)
pubs.funder-project-idZonMw (Vidi 016.156.308)
pubs.funder-project-idMaurits en Anna de Kock Stichting (2015-2)
pubs.funder-project-idCancer Research UK (C14303/A17197, A19274)


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Attribution 4.0 International (CC BY 4.0)
Except where otherwise noted, this item's licence is described as Attribution 4.0 International (CC BY 4.0)