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 *
Summary
Ductal cells have been proposed as a source of adult β cell neogenesis, but this has remained controversial. By combining lineage tracing, 3D imaging, and single-cell RNA sequencing (scRNA-seq) approaches, we show that ductal cells contribute to the β cell population over time. Lineage tracing using the Neurogenin3 (Ngn3)-CreERT line identified ductal cells expressing the endocrine master transcription factor Ngn3 that were positive for the δ cell marker somatostatin and occasionally co-expressed insulin. The number of hormone-expressing ductal cells was increased in
Akita
+/−
diabetic mice, and
ngn3
heterozygosity accelerated diabetes onset. scRNA-seq of Ngn3 lineage-traced islet cells indicated that duct-derived somatostatin-expressing cells, some of which retained expression of ductal markers, gave rise to β cells. This study identified Ngn3-expressing ductal cells as a source of adult β cell neogenesis in homeostasis and diabetes, suggesting that this mechanism, in addition to β cell proliferation, maintains the adult islet β cell population.
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