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dc.contributor.authorMessal, HA
dc.contributor.authorAlt, S
dc.contributor.authorFerreira, RMM
dc.contributor.authorGribben, C
dc.contributor.authorWang, VM-Y
dc.contributor.authorCotoi, CG
dc.contributor.authorSalbreux, G
dc.contributor.authorBehrens, A
dc.date.accessioned2020-08-05T11:02:38Z
dc.date.issued2019-02
dc.identifier.citationNature, 2019, 566 (7742), pp. 126 - 130
dc.identifier.issn0028-0836
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3902
dc.identifier.eissn1476-4687
dc.identifier.doi10.1038/s41586-019-0891-2
dc.description.abstractTubular epithelia are a basic building block of organs and a common site of cancer occurrence 1-4 . During tumorigenesis, transformed cells overproliferate and epithelial architecture is disrupted. However, the biophysical parameters that underlie the adoption of abnormal tumour tissue shapes are unknown. Here we show in the pancreas of mice that the morphology of epithelial tumours is determined by the interplay of cytoskeletal changes in transformed cells and the existing tubular geometry. To analyse the morphological changes in tissue architecture during the initiation of cancer, we developed a three-dimensional whole-organ imaging technique that enables tissue analysis at single-cell resolution. Oncogenic transformation of pancreatic ducts led to two types of neoplastic growth: exophytic lesions that expanded outwards from the duct and endophytic lesions that grew inwards to the ductal lumen. Myosin activity was higher apically than basally in wild-type cells, but upon transformation this gradient was lost in both lesion types. Three-dimensional vertex model simulations and a continuum theory of epithelial mechanics, which incorporate the cytoskeletal changes observed in transformed cells, indicated that the diameter of the source epithelium instructs the morphology of growing tumours. Three-dimensional imaging revealed that-consistent with theory predictions-small pancreatic ducts produced exophytic growth, whereas large ducts deformed endophytically. Similar patterns of lesion growth were observed in tubular epithelia of the liver and lung; this finding identifies tension imbalance and tissue curvature as fundamental determinants of epithelial tumorigenesis.
dc.formatPrint-Electronic
dc.format.extent126 - 130
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved
dc.subjectPancreatic Ducts
dc.subjectOrganoids
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectPancreatic Neoplasms
dc.subjectCell Transformation, Neoplastic
dc.subjectCell Polarity
dc.subjectMorphogenesis
dc.subjectStress, Mechanical
dc.subjectBiomechanical Phenomena
dc.titleTissue curvature and apicobasal mechanical tension imbalance instruct cancer morphogenesis.
dc.typeJournal Article
dcterms.dateAccepted2019-01-02
rioxxterms.versionofrecord10.1038/s41586-019-0891-2
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2019-02
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfNature
pubs.issue7742
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR
pubs.publication-statusPublished
pubs.volume566
pubs.embargo.termsNot known
dc.contributor.icrauthorBehrens, Axelen


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