Reprogramming the tumour microenvironment via mechanotransduction in pancreatic and liver cancers
File(s)
Author(s)
Cortes Lopez, Jose Ernesto
Type
Thesis
Abstract
Pancreatic ductal adenocarcinoma (PDAC), and Hepatocellular Carcinona (HCC) are the two most common types of hepatobiliary diseases. A common feature is that both develop in a highly fibrotic setting formed by a large and stiff mass known as tumour microenvironment. This tumour microenvironment modulates chemotherapy delivery, immune response, and tumour growth & dissemination.
Pancreatic stellate cells (PSCs) and hepatic stellate cells (HSCs) are the main resident cells in the tumour microenvironment of PDAC and HCC, respectively. In both diseases, activated stellate cells drive the formation of the desmoplastic reaction, by secreting abundant amounts of extracellular matrix and applying mechanical forces to stiffen and remodel the tissue architecture. This increases tissue tension and creates an environment of disrupted mechanical communication between stromal and cancer cells. Targeting the mechanobiology of stromal cells in PDAC and HCC to return the tumour microenvironment to physiological conditions seems then a pertinent approach to normalise the desmoplastic reaction in PDAC and HCC.
Finding novel mechanisms of action for already approved drugs offers the possibility of repositioning them to new clinical settings. In this work, two new mechanisms of action for tamoxifen and all trans-retinoic acid (ATRA) are presented. They involved GPER and RAR-, respectively. Modulating GPER or RAR- mediated mechanosignalling has emerged as a powerful target in PDAC and HCC paving the way to implement new therapeutic approaches, which are so urgently needed for these diseases. The fact that the signalling cascades downstream of GPER and RAR- are common to most types of cells suggests that these results might be applicable to other fibrotic disorders and solid cancers. These two new mechanisms change the focus of these two drugs from the cancer cells to the greater tumour microenvironment.
Pancreatic stellate cells (PSCs) and hepatic stellate cells (HSCs) are the main resident cells in the tumour microenvironment of PDAC and HCC, respectively. In both diseases, activated stellate cells drive the formation of the desmoplastic reaction, by secreting abundant amounts of extracellular matrix and applying mechanical forces to stiffen and remodel the tissue architecture. This increases tissue tension and creates an environment of disrupted mechanical communication between stromal and cancer cells. Targeting the mechanobiology of stromal cells in PDAC and HCC to return the tumour microenvironment to physiological conditions seems then a pertinent approach to normalise the desmoplastic reaction in PDAC and HCC.
Finding novel mechanisms of action for already approved drugs offers the possibility of repositioning them to new clinical settings. In this work, two new mechanisms of action for tamoxifen and all trans-retinoic acid (ATRA) are presented. They involved GPER and RAR-, respectively. Modulating GPER or RAR- mediated mechanosignalling has emerged as a powerful target in PDAC and HCC paving the way to implement new therapeutic approaches, which are so urgently needed for these diseases. The fact that the signalling cascades downstream of GPER and RAR- are common to most types of cells suggests that these results might be applicable to other fibrotic disorders and solid cancers. These two new mechanisms change the focus of these two drugs from the cancer cells to the greater tumour microenvironment.
Version
Open Access
Date Issued
2019-06
Date Awarded
2019-10
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
del Rio Hernandez, Armando
Sponsor
European Research Council
Grant Number
ERC grant 282051
Publisher Department
Bioengineering
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)