Replacing the need for patient-derived xenografts and matrigel organoid culture as preclinical models for breast cancer

Why did we fund this project?

This award aims to adapt a synthetic hydrogel for serum-free culture that can be used to support the growth of breast cancer stem cells in vitro rather than using xenograft mouse models for some studies.

A range of in vivo and in vitro models are used to study breast cancer to reflect different types and stages of the disease. Current in vivo models include xenografts, however, those using patient tissue have low engraftment rates creating a bias of cancers that are studied. Some studies using mouse xenograft models can be replaced using 3D in vitro approaches, but these currently require animal-derived matrices, such as collagen or Matrigel, to sustain the cellular phenotype. Professor Cathy Merry (Co-Investigator, University of Nottingham) has developed a customisable synthetic peptide hydrogel with NC3Rs funding. By adding various extracellular matrix components, such as proteins or sugars, in specific quantities the hydrogel can be composed to represent the environment of a breast cancer tumour in a patient.

Dr Robert Clarke is part of the Manchester Breast Centre, and he is using his networks to facilitate take up of the hydrogel model through the development of, online resources including videos, written protocols, FAQs and support pages. These will focus on culturing breast cancer cell lines, cells isolated from xenograft tumours and cells taken directly from patients with different molecular subtypes of breast cancer, including protocols for serum-free culture and breast cancer stem cell growth.

This award was made in collaboration with Cancer Research UK.

Most cells in your body are surrounded by a matrix of proteins and sugars. Cells interact with these and react to the elasticity and stiffness of the matrix. The extracellular matrix plays a key role in disease progression but is difficult to study in the lab. Studies are often carried out in human cells grown on plastic (2D) which poorly supports matrix interactions. To understand 3D matrix-driven behavior, labs rely on highly variable animal-derived artificial matrices or use animal models, including the growth of human cells transplanted into mice. Although these are more realistic, neither models the complex human tissue matrix well. We need to improve the 3D growth of cells within the laboratory and reduce the need for animal models.

We have developed a fully synthetic, reproducible gel that can mimic the matrix of human tissues. Breast cancer cells, along with other cell types, can be encapsulated and easily grown in the lab. This project aims to develop tools to share our mimics with research scientists throughout the world, providing cheap, functional and robust environments. This will allow researchers to test theories of cancer development, discover new targets for intervention and provide more realistic environments to screen therapeutics. To demonstrate the adaptability of our method we will also modify the gel formulations to (i) work in a fully animal product-free system (ii) to encapsulate breast cancer stem cells.

This project links the group who have developed the hydrogels with one of the world-leading groups researching breast cancer. This will ensure that we can reach and influence the global breast cancer research community and companies developing therapeutics. We will use a combination of on-line training packages and physical workshops to create a reliable way of sharing information. We anticipate significantly reducing the numbers of animals used in xenograft studies whilst also improving the relevance of work carried out in the laboratory.

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Skills and Knowledge Transfer grant

Status:

Active

Principal investigator

Dr Robert Clarke

Institution

The University of Manchester

Co-Investigator

Dr Catherine Merry
Dr Jennifer Ashworth

Grant reference number

NC/T001267/1

Award date:

Jul 2019 - Jun 2020

Grant amount

£74,983