Fully humanised 3D vascular perfused model for breast cancer modelling and therapeutic screening

Lead Research Organisation: University of Aberdeen
Department Name: Sch of Medicine, Medical Sci & Nutrition

Abstract

Breast cancer is the most common cancer affecting women. Scientists use a range of models to study this in the laboratory. This includes growing cells on plastic dishes or using animal models to mimic how breast cancer behaves. Neither model is ideal; growing cells on plastic is very different from how cells exist in the human body, while the animals used to mimic breast cancer are usually mice, which are very different from humans. We wish to implement a closer-to-patient model of breast cancer. This still uses cells growing in the laboratory, but these are growing in a way that is more similar to how they are in the human body. The cells grow in a three-dimensional environment, Currently, this three-dimensional environment contains animal-derived substances. In this project we wish to change the three-dimensional environment to make it completely free of any animal products. We can do this using a substance called a hydrogel. We can add different substances to the hydrogel to make it the same as the environment in which breast cancer cells grow in the body. Once we have achieved this we will make this environment closer still to how cancer cells are in the body. In the body cancer cells have a blood supply which allows them to receive a continuous flow of nutrients required to keep them alive. This is how drugs designed to kill cancer cells are also delivered. This is hard to achieve in the laboratory. We have overcome this by using an artificial blood substitute which we will introduce into our three-dimensional environment. This will produce a breast cancer model which has many similarities to how breast cancer cells grow in the human body, which we will be able to use routinely in our own labs. We want as many scientists as possible to know about this model and be able to use this, so we will organise training events where scientists from all over the UK can receive practical hands-on training in our technology so that are confident to start using this in their own labs. Finally, as university academics we are responsible for training the next generation of scientists so will introduced this technology into our teaching through lectures and practical sessions.

Technical Summary

Our technology has developed from two independently funded NC3Rs projects, uniting the Merry (developer) and Speirs (end user) groups. Merry has pioneered the development of self-assembling peptide hydrogels. These provide a fully tuneable matrix, devoid of any animal components, for disease modelling and therapeutic screening. Speirs is using a novel, synthetically vascularised, Organ-on-a-Chip screening platform, PerfusionPal, developed through NC3Rs CRACK IT by collaborator Vukasinovic and advanced though a current NC3Rs studentship to Speirs, to meet demands for physiologically closer in vitro platforms to model human tissues. The PerfusionPal model will be advanced by introduction of peptide hydrogels. Technological development and skills transfer will be driven by a postdoc. The hydrogel system will be incorporated into PerfusionPal and its effects tested experimentally, in perfused/unperfused conditions, against the current standard (Matrigel). We will identify optimal synthetic matrix components required to functionalise the 'naked' hydrogel, applying methods developed during Merry's current NC3Rs-funded project to generate gels with the preferred combination of physical and biochemical attributes to support the luminal A breast cancer model. The postdoc will visit Merry's lab to learn how to make hydrogels and apply this technology in Aberdeen. Cell viability assays will be performed, followed by live/dead Calcein AM/PI imaging. Further imaging will assess cell distribution throughout the hydrogel and identify changes in cell organisation due to the components selected to functionalise the hydrogel. A PerfusionPal platform, currently used by Speirs NC3Rs student in Leeds, will be relocated to Nottingham when the studentship ends (9/19). The system will be tested at both centres to ensure reproducibility. A free hands-on training workshop will introduce and promote uptake of the technology to the wider scientific community, with bursaries provided for ECRs.

Publications

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