Application of a 3D hydrogel-based model to replace use of animals for passaging patient-derived xenografts

Jones, Sal (2021) Application of a 3D hydrogel-based model to replace use of animals for passaging patient-derived xenografts. PhD thesis, University of Nottingham.

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Abstract

Currently, in vivo mouse models are the gold standard for testing cancer treatments before progression to human trials, often using tissue derived directly from patient tumours (patient-derived xenografts, PDXs) propagated in mice to generate sufficient cells for an experiment. A 3D in vitro system for tumour passage would reduce animal use and provide an alternative means of expansion, with the additional benefit of being capable of maintaining a human signalling environment throughout.

This 3D in vitro cancer model for propagation of patient-derived cells, based on a synthetic self-assembling peptide gel and using human extracellular components, allows the formation of a fully characterised, tailorable tumour microenvironment. Unlike many existing 3D cancer models the peptide gel is inert apart from molecules and motifs deliberately added or produced by cells within the model.

Breast cancer PDXs were shown to be capable of expansion over several passages in the peptide gel, and contaminating mouse cells are rapidly removed by successive passages. The resulting human cells were shown to be compatible with a range of common assays useful for assessing survival, growth and maintenance of heterogeneity. Experiments were also performed to probe practical and effective approaches for inclusion of relevant human stromal cells to increase the model’s resemblance to patient tumours.

With further development, this hydrogel model can be tailored by addition of tumour microenvironment-relevant molecules and cell types. Based on these initial findings, following further work to confirm maintenance of cell heterogeneity, genotypes and phenotypes across passage, the hydrogel has potential to provide an effective and practical breast cancer model for passage of PDXs which will have the added benefits of being relatively cheap, fully-defined and free of animal products, with potential for further development to cover other cancer types.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Grabowska, Anna M.
Merry, Cathy L.R.
Keywords: 3D cancer model, breast cancer, patient-derived xenografts
Subjects: QS-QZ Preclinical sciences (NLM Classification) > QZ Pathology
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Medicine
Item ID: 65724
Depositing User: Jones, Sal
Date Deposited: 04 Aug 2021 04:43
Last Modified: 04 Aug 2021 04:43
URI: http://eprints.nottingham.ac.uk/id/eprint/65724

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