Investigation into the interplay between cancer cells and their associated fibroblasts in malignant pleural mesothelioma: therapeutic implications
File(s)
Author(s)
Chrisochoidou, Yakinthi
Type
Thesis
Abstract
Malignant pleural mesothelioma (MPM) is a highly aggressive malignancy with a median
survival of 12 months following diagnosis. The UK is amongst the leading countries for mesothelioma-caused mortality and the standard-of-care for the disease has not been improved for nearly two decades. A main contributor to poor disease outcome is the extensive associated fibrosis which hinders treatment success and gradually causes loss of respiratory function. Hence, targeting this process in addition to tumour cell viability may be of great therapeutic benefit.
This study investigated the interplay between mesothelioma cells and their associated
fibroblasts (CAFs), the main contributor to the fibrotic process, using a variety of proteomics
profiling approaches. This revealed SRC, PDGFR and VEGFR along with the PI3K/mTOR signalling
cascade as key intracellular mediators of the cross-talk between MPM cancer cells and CAFs.
Extracellularly, the identified secreted cytokines and growth factors promote angiogenesis
(ANGPT2, END), extracellular matrix (ECM) remodelling (BSG, MMPs, LOX2), propagation of the pro-fibrotic signalling (PDGFA, VEGFA, OPN, FGFs, IL-17A) and TME immunosuppression (CXCL12, MIF, M-CFS, MCP1, VEGFA, TGFβ). Last, but not least, analysis of components of the CAF-derived ECM highlighted the released molecules and mechanisms CAFs employ to promote
tumourigenesis according to the requirements of the TME, particularly through regulation of the
bioavailability of TGFβ and PDGF in the TME.
Based on these combined proteomics data, a panel of 14 small-molecule inhibitors against
selected identified targets was assembled and their efficiency in targeting the viability of 3D
MPM/CAF spheroid co-cultures and the fibrotic response tested. Drugs were tested both as single agents and in 1 to 1 combinations. Our results show that combination of the mTOR inhibitor Vistusertib with either the SRC inhibitor Saracatinib or the tyrosine kinase inhibitor Cediranib was more potent than the current standard-of-care for MPM, Cisplatin/Pemetrexed. Additionally, unlike the latter combination, the Vistusertib-based combinations prevented CAF-induced drug resistance in 3D culture. In short, the findings of this thesis propose novel cytotoxic and anti-fibrotic therapeutic strategies for MPM.
survival of 12 months following diagnosis. The UK is amongst the leading countries for mesothelioma-caused mortality and the standard-of-care for the disease has not been improved for nearly two decades. A main contributor to poor disease outcome is the extensive associated fibrosis which hinders treatment success and gradually causes loss of respiratory function. Hence, targeting this process in addition to tumour cell viability may be of great therapeutic benefit.
This study investigated the interplay between mesothelioma cells and their associated
fibroblasts (CAFs), the main contributor to the fibrotic process, using a variety of proteomics
profiling approaches. This revealed SRC, PDGFR and VEGFR along with the PI3K/mTOR signalling
cascade as key intracellular mediators of the cross-talk between MPM cancer cells and CAFs.
Extracellularly, the identified secreted cytokines and growth factors promote angiogenesis
(ANGPT2, END), extracellular matrix (ECM) remodelling (BSG, MMPs, LOX2), propagation of the pro-fibrotic signalling (PDGFA, VEGFA, OPN, FGFs, IL-17A) and TME immunosuppression (CXCL12, MIF, M-CFS, MCP1, VEGFA, TGFβ). Last, but not least, analysis of components of the CAF-derived ECM highlighted the released molecules and mechanisms CAFs employ to promote
tumourigenesis according to the requirements of the TME, particularly through regulation of the
bioavailability of TGFβ and PDGF in the TME.
Based on these combined proteomics data, a panel of 14 small-molecule inhibitors against
selected identified targets was assembled and their efficiency in targeting the viability of 3D
MPM/CAF spheroid co-cultures and the fibrotic response tested. Drugs were tested both as single agents and in 1 to 1 combinations. Our results show that combination of the mTOR inhibitor Vistusertib with either the SRC inhibitor Saracatinib or the tyrosine kinase inhibitor Cediranib was more potent than the current standard-of-care for MPM, Cisplatin/Pemetrexed. Additionally, unlike the latter combination, the Vistusertib-based combinations prevented CAF-induced drug resistance in 3D culture. In short, the findings of this thesis propose novel cytotoxic and anti-fibrotic therapeutic strategies for MPM.
Version
Open Access
Date Issued
2021-04
Date Awarded
2021-10
Copyright Statement
Creative Commons Attribution NonCommercial NoDerivatives Licence
Advisor
Pardo, Olivier E.
Sponsor
Imperial College London
Publisher Department
Department of Surgery & Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)