Tissue curvature and apicobasal mechanical tension imbalance instruct cancer morphogenesis

Abstract

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 *

Cell-based Simulations of Biased Epithelial Lung Growth

“…The requirement for high cortical tension is consistent with the observation that biased outgrowth is lost in mutants that express a constitutive active form of KRas (Shh cre/+ ; KRas LSL/+ ) [4]. Constitutive active KRas has previously been shown to result in a redistribution of phosphorylated myosin light chain 2 (pMLC2) inside cells of pancreatic ducts [28], which may result in reduced cortical tension on the apical side of the epithelium, where all cell divisions occur [29].…”

“…KRas signaling in airway epithelial cells has previously been linked to changes in cell shape and motility by affecting cortical actin [27]. Expression of a constitutive active form of KRas (KRas G12D ) in pancreatic ducts results in a redistribution of phosphorylated myosin light chain 2 (pMLC2) inside the cell, so that its concentration declines on the apical side and increases on the basal side [28]. Constitutive active KRas may thus reduce cortical tension on the apical side of the epithelium, where all cell divisions occur [29].…”

Local light-activation of the Src oncoprotein in an epithelial monolayer promotes collective extrusion

“…However, in that case, the tissue deformation is triggered by the interface contractility between two distinct cell populations. Very recently, Messal et al analyzed how clusters of Krastransformed cells trigger morphological changes in tissue architecture of pancreatic ducts 56 . Our results are consistent with their observation of endophytic lesions made of transformed cells growing inwards for ducts of large diameter.…”

Progenitors oppositely polarize WNT activators and inhibitors to orchestrate tissue development

“…Intensity plots were generated like in (Messal et al 2019) using the plot profile tool from Fiji (NIH) and measuring intensities of a minimum of 3 basal cells per developing follicle (from a minimum of developing skin from 3 embryos). Briefly, optical sections of whole-mount 40x confocal images were converted into composite images in which MYC-tag (or FZD10) was in the red (or green) channel and DAPI (which labels the DNA) in the blue.…”