Blyth Rhianna R R, Laversin Stèphanie A, Foxall Russell B, Savva Constantinos, Copson Ellen, Cutress Ramsey I, Birts Charles N, Beers Stephen A
Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK.
School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK.
NPJ Breast Cancer. 2025 May 30;11(1):50. doi: 10.1038/s41523-025-00766-3.
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.
肥胖与更差的乳腺癌预后及降低的治疗效果相关。然而，导致肥胖相关治疗抵抗的机制仍不清楚；部分原因是缺乏能够重现肥胖肿瘤微环境的合适模型。为了解决这一问题，我们开发了一种肥胖相关乳腺癌的三维体外模型，以研究生物学机制并用作药物测试工具。通过在胶原蛋白基质中将脂肪细胞球体与乳腺肿瘤细胞、肌上皮细胞、巨噬细胞和成纤维细胞共培养，建立了一种五元培养系统。肿瘤细胞和巨噬细胞浸润脂肪细胞球体，重现了肥胖患者典型的炎症脂肪边界。然后将该模型评估为药物测试平台。与非肥胖培养物相比，肥胖培养物对二甲双胍表现出更高的敏感性，相反，对紫杉醇具有抗性。这种三维器官型模型有效地重现了肥胖脂肪肿瘤微环境的关键特征，为探究肥胖相关治疗抵抗的潜在机制提供了一个有用的工具。
