3D Extracellular matrix remodelling by breast cancer cells: Investigating the combined mechanobiological and metabolic effects of obesity
Supervisor: Dr Nadia Soulioti
School: Engineering
Description:
Obesity affects over 650 million adults and increases breast cancer risk by 30-50% in postmenopausal women. Furthermore, this condition has been identified as the second-highest preventable risk factor for cancer in the UK. With global trends suggesting the obese population could rise to 1.85 billion by 2050, understanding the correlation between obesity and cancer aggressiveness grows as a more pressing issue, particularly considering how current cancer treatments are less effective in obese patients.
The extracellular matrix (ECM), namely the structural scaffold surrounding cells, plays a crucial role, as both its physical structure and biochemical signals influence how cancer cells invade surrounding tissues. This project will investigate how breast cancer cells remodel 3D collagen networks under conditions mimicking lean and obese environments. Our laboratory established that breast cancer cells with different malignancy levels exhibit distinct ECM remodelling patterns on 2D collagen substrates. However, 2D systems fail to recapitulate 3D constraints present in vivo. Furthermore, while obesity exacerbates cancer progression, the specific contributions of metabolic dysfunction versus altered mechanical microenvironment remain poorly differentiated. This project addresses these gaps using 3D scaffolds with and without obesity-associated biochemical factors.
Using temperature-controlled collagen gelation, we will fabricate architecturally distinct scaffolds: warm-cast scaffolds featuring dense networks of thin fibres mimicking restrictive tumour environments, and cold-cast scaffolds with porous thick-fibre networks resembling permissive stroma. MDA-MB-231 breast cancer spheroids will be embedded within these matrices and cultured with adipose-conditioned media from lean and obese mouse models. Time-lapse confocal microscopy will track spheroid invasion and matrix reorganisation, while immunostaining for mechanotransduction markers (YAP/TAZ, vimentin) and MMP-2 ELISA will quantify cellular responses and matrix degradation.
By systematically varying scaffold architecture and obesity-associated factors, this project will decouple pure mechanobiological effects from metabolic influences, revealing how these factors synergistically drive cancer progression. Expected outcomes include identification of architecture-obesity combinations that produce the most aggressive phenotypes, providing insight into optimal therapeutic targets. As novel therapies targeting obesity-driven ECM remodelling have shown promise against cancer, this study may inform future treatment strategies that address the current inequalities in outcomes between obese and lean patients.