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James, Jenna (2021) Structure-function correlation and biophysical analysis of a novel 3D in vitro leukaemia model. PhD thesis, University of Nottingham.

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Abstract

The prognosis for relapsed acute myeloid leukaemia (AML) is poor, with available treatments unable to fully eradicate the leukaemic stem cells (LSCs) from which the heterogeneous AML cell types are considered to arise. LSCs evade treatment by hiding within the bone marrow niche, a property current 2D in vitro models fail to recapitulate. As the field of cancer research continues to acknowledge the disparate response of leukaemia cells to treatments in vitro as compared to in vivo, research requires defined and adjustable synthetic models in which to improve our understanding of the impact of mechanical cues in AML treatment response.

By use of a synthetic self-assembling peptide hydrogel (FEFEFKFK) of modifiable viscosity and composition, this project developed and utilised a 3D model of the bone marrow niche to screen repurposed FDA-approved drugs. The unmodified peptide gels contained no inherent matrix proteins or growth factors, and as such offered the unique ability to observe the influence of 3-dimensions on cell behaviour independent of binding motifs. Using novel biophysical techniques based on optical tweezers, the microrheological properties of the peptide gels were quantified, and subsequently demonstrated the stiffness of the model to be comparable with that of the bone marrow. The resulting 3D models showed significantly higher leukaemic cell proliferation than in 2D liquid culture or in higher stiffness gels. Finally, the models were used to mimic ‘early stage’ and ‘established’ AML and treated with FDA-approved drugs. These results identified a variation of drug efficacy between the models and 2D liquid culture, suggesting the unmodified 3D environment influences AML cell sensitivity to drug treatment.

Pathophysiologically relevant in vitro cancer models for drug discovery and development is one of the major challenges facing researchers in the desire to improve the low translation of therapies into clinic. Here we present a novel 3D AML model offering unique insight into the impact of mechanical characteristics on cell behaviour, proliferation, and drug sensitivity. Future work following from these results will continue to obtain an improved mechanistic understanding of 3D models in AML drug repurposing and resistance, with the aim to develop the 3D peptide gel for patient-derived tissue.

Item Type:	Thesis (University of Nottingham only) (PhD)
Supervisors:	Thompson, Alexander Wright, Amanda Merry, Cathy Arkill, Kenton
Keywords:	Model bone marrow niche; Acute myeloid leukaemia; Drug response; Cancer models; Drug discovery
Subjects:	W Medicine and related subjects (NLM Classification) > WH Hemic and lymphatic system
Faculties/Schools:	UK Campuses > Faculty of Engineering > Department of Electrical and Electronic Engineering UK Campuses > Faculty of Medicine and Health Sciences > School of Medicine
Item ID:	65327
Depositing User:	James, Jenna
Date Deposited:	04 Aug 2021 04:42
Last Modified:	04 Aug 2021 04:42
URI:	https://eprints.nottingham.ac.uk/id/eprint/65327

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