发表机构
Cornell University; Yale University; Weill Cornell Medicine; Dartmouth Geisel School of Medicine; Emory University; City College of New York（康奈尔大学; 耶鲁大学; 威尔康奈尔医学院; 达特茅斯盖泽尔医学院; 埃默里大学; 纽约市立大学）
机构由 AI 辅助整理，请以论文原文为准。AI 中文总结
本研究结合实验与DEM模拟，发现肥胖引起的组织压力及肿瘤诱导的脂质损失在物理上重塑白色脂肪组织，从而加速乳腺癌侵袭，且肥胖可能加剧此效应。
AI 中文摘要
肥胖是乳腺癌的主要风险因素，然而肥胖相关的白色脂肪组织（WAT）物理性质变化如何影响肿瘤侵袭仍知之甚少。在此，我们结合实验和计算方法来研究这一问题。利用小鼠模型和人类乳房切除标本，我们表明肥胖不仅增加脂肪细胞大小，还增加其非球形度。我们观察到，肿瘤条件培养基在体外驱动脂肪细胞脂质损失和去分化，使其转变为肌成纤维细胞样细胞；并且在高脂饮食喂养的小鼠中，脂肪细胞在体内对乳腺肿瘤的反应中脂质损失速率高于正常饮食喂养的小鼠。随后，我们开发了离散元法（DEM）模拟，以理解这些肥胖诱导的细胞和组织性质变化如何在高脂和正常饮食条件下改变乳腺癌侵袭。在DEM模拟中，脂肪细胞被建模为可变形多边形和多面体，癌细胞在二维和三维中分别被建模为软粘性圆盘和球体。侵袭由癌细胞增殖驱动，肿瘤诱导的脂质损失被建模为脂肪细胞大小的相应减小。DEM模拟表明，肥胖相关的组织压力增加诱导脂肪细胞变形，与实验数据中升高的非球形度一致。在小的脂质损失速率下，癌症侵袭程度受组织压力影响较弱。然而，在足够大的脂质损失速率下，我们发现组织压力加速癌症侵袭。综合这些结果，表明脂质损失在物理上重塑WAT以促进乳腺癌侵袭，并且肥胖可能加剧这一效应。
英文摘要
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.
