Tissue curvature and apicobasal mechanical tension imbalance instruct cancer morphogenesis.
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ICR Authors
Authors
Messal, HA
Alt, S
Ferreira, RMM
Gribben, C
Wang, VM-Y
Cotoi, CG
Salbreux, G
Behrens, A
Alt, S
Ferreira, RMM
Gribben, C
Wang, VM-Y
Cotoi, CG
Salbreux, G
Behrens, A
Document Type
Journal Article
Date
2019-02-07
Date Accepted
2019-01-02
Abstract
Tubular epithelia are a basic building block of organs and a common site of cancer occurrence1-4. 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.
Citation
Nature, 2019, 566 (7742), pp. 126 - 130
Source Title
Publisher
NATURE PUBLISHING GROUP
ISSN
0028-0836
eISSN
1476-4687