Tubular epithelia are a basic building block of organs and a common site of cancer occurrence 1-4. During tumourigenesis, transformed cells overproliferate and epithelial architecture is disrupted. The biophysical parameters underlying the adoption of abnormal tumour tissue shapes are, however, not known. Here we show 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 of tissue architecture during cancer initiation, we developed a three-dimensional (3D) whole organ imaging technique allowing tissue analysis at single cell resolution. Oncogenic transformation of pancreatic ducts led to two types of neoplastic growth: exophytic lesions expanding outwards from the duct, and endophytic lesions growing inwards to the ductal lumen. Myosin activity was higher apically than basally in wildtype cells but upon transformation, this gradient was lost in both lesion types. 3D vertex model simulations and a continuum theory of epithelial mechanics, incorporating the cytoskeletal changes observed in *
Pancreatic ductal adenocarcinoma (PDAC) shows great cellular heterogeneity, with pronounced epithelial and mesenchymal cancer cell populations. However, the cellular hierarchy underlying PDAC cell diversity is unknown. Here we identify the tetraspanin CD9 as a marker of PDAC tumour-initiating cells. CD9 high cells had increased organoid formation capability, and generated tumour grafts in vivo at limiting dilutions. Tumours initiated from CD9 high cells recapitulated the cellular heterogeneity of primary PDAC, whereas CD9 low cells only produced duct-like epithelial progeny. CD9 knockdown decreased the growth of PDAC organoids, and heterozygous CD9 deletion in Pdx1-Cre; LSL-KRas G12D ; p53 F/F mice prolonged overall survival. Mechanistically, Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
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