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Tuneable 3D biocompatible scaffolds for biological and biophysical solid-tumour microenvironment studies; applications in Ovarian Cancer / FRANCESCA PARADISO

Swansea University Author: FRANCESCA PARADISO

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DOI (Published version): 10.23889/SUthesis.60122

Abstract

Recently, three-dimensional (3D) tumour models mimicking the tumour microenvironment and reducing the use of experimental animals have been developed generating great interest to appraise tumour response to treatment strategies in cancer therapy. As tumours have distinct mechanics compared to normal...

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Published: Swansea 2022
Institution: Swansea University
Degree level: Doctoral
Degree name: Ph.D
Supervisor: Francis, Lewis ; Taraballi, Francesca
URI: https://cronfa.swan.ac.uk/Record/cronfa60122
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Abstract: Recently, three-dimensional (3D) tumour models mimicking the tumour microenvironment and reducing the use of experimental animals have been developed generating great interest to appraise tumour response to treatment strategies in cancer therapy. As tumours have distinct mechanics compared to normal tissues, biomaterials have also been utilized in 3D culture to model the mechanical properties of the tumour microenvironment, and to study the effects of extracellular matrix (ECM) mechanics on tumour development and progression. Mechanical cues regulate various cell behaviours through mechanotransduction, including proliferation, migration, and differentiation. In the context of cancer, both stromal cells (cancer associated fibroblasts) and tumour cells remodel the ECM and change its mechanical properties, and the altered mechanical niche in turn is likely to influence tumour progression. In this study, bovine derived collagen type I and Jellyfish derived marine collagen sources, were tested as biomaterial candidates for cancer studies, moulded to porous scaffolds with tuneable mechanical properties. The resulting interconnected network of collagen fibre constructs, fabricated using lyophilisation provide good control of scaffolding architecture, pore sizes range, high porosity levels, high level of cell viability and low production cost. Importantly these sponge scaffolds were, in the form of 3D models, compatible with a host of cellular and molecular biology assays used to investigate mechanical and biological effects of collagen crosslinking and (hyaluronic acid) HA inclusion on both fibroblasts and ovarian cancer cells. Stromal cells and cancer cells respond differently to the altered stiffness of their local microenvironment. Fibroblasts, once activated with TGF1, converge toward a ‘senescent-like phenotype’, blocking migration and matrix remodelling and promote tumour progression, probably through the secretion of tumour-promoting signals, in stiffer mechanical environments. Cancer cells, of both epithelial and mesenchymal phenotype, respond to increased local matrix stiffness by increasing proliferation while, at the same time, becoming more susceptible to treatment. Mechanically informative scaffolds resemble the physical characteristics of both normal and pathological ovarian tissue mechanics, where ovarian cancer originates. Physical changes observed in the later stage of ovarian cancer disease progression may therefore be fundamental for the increased cancer proliferation that drives metastatic progression, however opening an interesting window for cancer treatment. Bio-physical inclusive models not only lead the path to unveil complex interactions of biophysical and biological signals in the tumour microenvironment, but they represent a highly informative and effective platform to test novel target therapies with effective costs and high throughput. They can accommodate coculture systems and potentially patients-derived cell cultures, providing a platform to test current and new drugs and to evaluate drug efficacy following a precision medicine approach.
Item Description: ORCiD identifier: https://orcid.org/0000-0001-6926-1119
College: Faculty of Medicine, Health and Life Sciences