Development and characterisation of a novel 3D in vitro model of obesity-associated breast cancer as a tool for drug testing

Abstract

Abstract Obesity is associated with worse breast cancer outcomes and decreased therapeutic efficacy. However, the mechanisms driving obesity-associated therapy resistance remain unclear; in part due to a lack of suitable models that recapitulate the obese tumour microenvironment. To address this, we developed a 3D in vitro model of obesity-associated breast cancer, to investigate biological mechanisms and to use as a drug testing tool. A penta-culture system was developed by co-culturing adipocyte spheroids with breast tumour cells, myoepithelial cells, macrophages, and fibroblasts in a collagen matrix. Tumour cells and macrophages infiltrated adipocyte spheroids, replicating the inflamed-adipose border typical of obese patients. This model was then assessed as a drug testing platform. Obese cultures exhibited increased sensitivity to metformin and, conversely, resistance to paclitaxel, compared to non-obese cultures. This 3D organotypic model effectively recapitulates key features of the obese adipose tumour microenvironment, providing a useful tool to interrogate mechanisms underpinning obesity-related therapy resistance.