Development and Validation of a 3D Pancreatic Cancer Cell Organoid System for Radiation Response Studies to Support Advanced Radiotherapy
Creators: name: WISHART, GABRIELLE AMELIA
Publisher: name: University of Surrey
Year: 2022

description: Patient response to radiotherapy treatment varies from tumour to tumour and patient to patient
description: but is highly influenced by the tumour microenvironment (TME). The TME is a complex
description: ecosystem of biological, biophysical, biomechanical and biochemical milieus that enrich
description: tumour survival and influence treatment response. In vitro 3D models of cancer are emerging
description: to more readily recapitulate complex hallmarks of the TME, as compared to traditional 2D
description: cell culture and animal models. This novel field of tissue engineering is advancing as a
description: promising biomimetic approach for pre-clinical treatment screening and is particularly
description: appropriate for cancers that house a uniquely complex TME, such as pancreatic ductal
description: adenocarcinoma (PDAC). PDAC is a cancer of unmet clinical needs with dismal survival
description: statics. The PDAC TME encompasses specific hallmarks such as hypoxia that impair the
description: efficacy of radiotherapy treatment. The use of radiotherapy for PDAC is thought to be still
description: evolving, with novel treatments such as MR-guided radiotherapy emerging for more specific
description: tumour targeting. However, for MR-guided radiotherapy, the presence of static magnetic
description: fields (SMF) in combination with radiation is understudied and not fully understood. Reliable
description: biomimetic models of the TME to test new radiation delivery strategies and their biology
description: endpoints are required to more accurately predict in vivo responses of patients.<br>
description: <br>
description: This work describes the development and validation of a hypoxic, novel polymer
description: (polyurethane) based highly macroporous scaffold system for long-term analysis of PDAC
description: radiation responses for the first time. Polyurethane (PU) scaffolds were fabricated via
description: thermally induced phase separation (TIPS) and surface modified with fibronectin for realistic
description: TME recapitulation. PDAC cell lines (PANC-1 and ASPC-1) were seed and cultured in PU
description: scaffolds in a hypoxic chamber (5%, 0-5%, and 1% oxygen) and were exposed to irradiation
description: (6 Gy). Live/dead and Caspase 3/7 analysis in line with a hypoxic biomarker (HIF-1a) post
description: treatment, revealed hypoxia associated radio-resistance. Furthermore, towards understanding
description: the biological response to MR-guided radiotherapy the presence of SMF (1.5 T) was tested in
description: combination with irradiation (6 Gy) to find radiation and SMF synergism. Furthermore, this
description: scaffold is applied to an in vitro skin biomimetic model to evaluate the versatility of such
description: models for not only the cancer field but for clinical and cosmetic living skin equivalent
description: testing. Overall, this thesis reports the use of a novel PU scaffold to investigate advanced
description: tissue engineering for radiation response studies and as a hybrid bi-layer model of the skin.