Developing preclinical peptide hydrogel models of breast cancer metastasis to bone using patient-derived tumour cells and xenografts

Human tumours have complex interplay between the extracellular matrix (ECM) and cellular components. The Clarke lab has used patient-derived xenograft (PDX) tumour models in immune-deficient mice to recapitulate complex microenvironments, including the bone metastatic niche (Eyre et al., Nature Comm., 2019). However, PDX models are subject to limitations including a lack of immune function and human tumour interaction with a mouse microenvironment. The need for a superior in vitro alternative is pressing considering the dominance of PDX models as a tool for personalized therapy. 'Xeno-patient' cohorts are the most clinically relevant animal models in cancer drug discovery (Byrne et al., Nature Reviews Cancer, 2017). Even with its limitations, the breast cancer field uses xenograft models routinely. An alternative is to use breast organoids grown in vitro from patient-derived breast cancer cells or xenografts (Sachs et al., Cell, 2018; Guillen et al., BioRxiv, 2021). The organoids will be encapsulated in peptide hydrogels, which we anticipate will be superior to matrigel (gold standard) since its stiffness can be tuned to match breast cancer ECM physical states. The peptide gel technology, will be modified with or without osteogenic factors to model the bone metastatic niche. In addition, human cellular and extracellular matrix components will be introduced with patient-derived breast cancer cells to create a functional and amenable in vitro platform for multiple applications. These applications include investigating bone metastatic breast cancer biology and screening of targeted therapies in clinically relevant patient samples, providing a platform for precision medicine and testing of personalised treatments.

There are numerous beneficiaries of this Advanced Biomedical Materials CDT. Firstly and of short term impact are the PhD students themselves. They will receive extensive research specific and professional/transferable skills training throughout the 4 years of the programme. They will have access to state of the art facilties and world leading academics, industry and clinicians. The training and potential placements are designed to maximise the impact of their research in terms of dissemination and movement of their research along the translation pathway.

Longer term benefits are that this distinct cohort will become the future UK Biomedical Materials leaders and be able to use their bespoke training and network within the cohort to collaborate on future worldwide funding opportunities and drive UK research in this area.

UK and international academics will benefit as they will gain the next generation of highly skilled postdoctoral researchers with knowledge and expertise not only in their specific research area but of industry, regulatory and clinical aspects.

UK and international industry will benefit - in the short term they will gain academic based research to further develop products and in the longer term have a pool of highly skilled graduates.

Clinicians will benefit from collaborative research and also the development of new and novel products to enhance the treatment of a variety of trauma and disease based needs from biomaterials.

The public will benefit as end users as patients that will have their quality of life improved from the products developed in the CDT and will be educated in novel technologies and materials to repair the human body. The UK economy will benefit from the reduced healthcare costs associated with the new and improved medical products developed in this CDT and subsequently from the trained graduates. The UK economy will also benefit from the increased revenue from medical sales products from the UK industrial partners we will be working with.

The impact of this CDT will be realised by direct academic, clinical and industrial engagement with the students allowing efficient and state of the at training and fast translation of developing products. Students will also be trained in knowledge exchange and will use these skills to disseminate their research to, and liaise with, the key stakeholders - the academic, industrial, clinical and public sectors. We will ensure widening participation routes are addressed in this CDT in order to include equality and diversity not only in our initial CDT student cohort but in future researcher generations to come.