3D tumour models for the assessment of tumour micro-environment targeted therapies


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David Onion (1), Richard Argent (1), Rajendra Kumari (1), Amy Axel (2), Brett Hall (2), Sue Watson (1)
Ex Vivo Cancer Pharmacology Centre of Excellence, Division Of Pre-Clinical Oncology, University of Nottingham, Nottingham, United Kingdom (1), OthoBiotech, Oncology Research & Development, Beerse, Belgium (2)

Background

It is becoming increasingly apparent that the interaction between the tumour and the surrounding stromal cells is critical to tumour growth, invasion and metastasis. As a consequence, tumour-microenvironment targeted therapies and therapies which disrupt the paracrine signalling pathways that support tumour growth are under development. Current pre-clinical in vitro and in vivo tumour models lack human stromal cells and so are inadequate for the assessment of novel tumour microenvironment targeted therapies

Method

We have developed a novel 3D matrix reconstitution assay, where the paracrine interaction between tumour derived fibroblasts and epithelial cells are restored, allowing the real-time assessment of tumour-microenvironment driven tumour growth in the presence of targeted therapies.

Results

Primary tumour associated fibroblasts and mesenchymal stem cells drive growth and proliferation of non-small cell lung cancer cell lines of adenocarcinoma (A549, NCI-H358, NCI-H460) and squamous subtypes (SK-MES1) as well as early stage disease (NCI-H322M). The paracrine interaction promotes 3D structure formation and invasion into laminin rich basement membrane extract. Using fluorescent cell labelling and real-time viability assays the 3D matrix reconstitution assay allows the rapid and scalable assessment of targeted therapies in comparison to platinum doublet standards of care in the context of tumour micro-environment driven growth.

Conclusion

The 3D matrix reconstitution assay provides a more accurate model for pre-clinical testing of therapies which target the tumour microenvironment or the downstream pathways of their paracrine interaction with tumour cells.

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