Mechanical tension in pancreatic ductal adenocarcinoma progression
File(s)
Author(s)
Vella, Alain
Type
Thesis
Abstract
Healthy biological tissues are constantly acted upon by physiological mechanical stimuli. Perturbations of these mechanical stimuli are however implicated in diseases such as cancer. Amongst these stimuli, accumulated solid stresses are a hallmark of pancreatic ductal adenocarcinoma (PDAC) and are increasingly being recognised as a novel and distinct promoter of tumour growth and spread. It is hypothesised that tensile stresses which accumulate at the periphery of PDAC tumours promote activation of the stroma in adjacent healthy tissues, laying the groundworks for PDAC progression.
This project modelled the growth of PDAC tumours computationally and found that tissues in the peritumoural stroma are subjected to high in-plane tensile stresses. Uniaxial stretching was applied to cell cultures in vitro to analyse the effect of these stresses. Stretching downregulated E-cadherin expression in epithelial cells, suggesting that mechanical tension may contribute to epithelial to mesenchymal transition. Subsequent stretching of pancreatic stellate cells (PSCs), key regulators of the PDAC physical microenvironment, on an equibiaxial cell stretching device evidenced increases in collagen I protein synthesis as well as an NF-κB mediated upregulation of vascular growth factor A (VEGF-A) expression. By establishing that stretching of PSCs induces pro-fibrotic and pro-angiogenic behaviours, these novel findings within the context of PDAC support the hypothesis that mechanical tension contributes to stromal activation in PDAC. The findings from this research are intended to support studies which seek to clarify the prognostic role of activated PDAC stroma and the merits of stromal modification.
This project modelled the growth of PDAC tumours computationally and found that tissues in the peritumoural stroma are subjected to high in-plane tensile stresses. Uniaxial stretching was applied to cell cultures in vitro to analyse the effect of these stresses. Stretching downregulated E-cadherin expression in epithelial cells, suggesting that mechanical tension may contribute to epithelial to mesenchymal transition. Subsequent stretching of pancreatic stellate cells (PSCs), key regulators of the PDAC physical microenvironment, on an equibiaxial cell stretching device evidenced increases in collagen I protein synthesis as well as an NF-κB mediated upregulation of vascular growth factor A (VEGF-A) expression. By establishing that stretching of PSCs induces pro-fibrotic and pro-angiogenic behaviours, these novel findings within the context of PDAC support the hypothesis that mechanical tension contributes to stromal activation in PDAC. The findings from this research are intended to support studies which seek to clarify the prognostic role of activated PDAC stroma and the merits of stromal modification.
Version
Open Access
Date Issued
2023-10
Date Awarded
2024-09
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
del Río Hernández, Armando
Publisher Department
Bioengineering
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)