Tumor-induced lipid loss physically accelerates breast cancer invasion into mammary adipose tissue

Abstract

Obesity is a major risk factor for breast cancer, yet how obesity-associated changes in the physical properties of white adipose tissue (WAT) influence tumor invasion remains poorly understood. Here, we combine experimental and computational approaches to investigate this question. Using mouse models and human mastectomy samples, we show that obesity not only increases adipocyte size, but also asphericity. We observe that tumor-conditioned media drives lipid loss and dedifferentiation of adipocytes into myofibroblast-like cells in vitro and that adipocytes in high-fat diet-fed mice lose lipid at a faster rate than those in normal diet-fed mice in response to mammary tumors in vivo. We then develop discrete element method (DEM) simulations to understand how these obesity-induced changes in cell and tissue properties alter breast cancer invasion under high-fat and normal diet conditions. In DEM simulations, adipocytes are modeled as deformable polygons and polyhedra, and cancer cells are modeled as soft, adhesive disks and spheres in two and three dimensions, respectively. Invasion is driven by cancer cell proliferation and tumor-induced lipid loss is modeled as corresponding decreases in adipocyte size. DEM simulations indicate that obesity-associated increases in tissue pressure induce adipocyte deformation, consistent with elevated asphericity in experimental data. At small lipid loss rates, the degree of cancer invasion is only weakly affected by tissue pressure. However, at sufficiently large lipid loss rates, we find that tissue pressure accelerates cancer invasion. Together, these results suggest that lipid loss physically remodels WAT to facilitate breast cancer invasion, and that obesity may exacerbate this effect.