Emergence of nanoscale viscoelasticity from single cancer cells to established tumors.
Emergence of nanoscale viscoelasticity from single cancer cells to established tumors.
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DOI：
10.1016/j.biomaterials.2023.122431
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发表时间：
2023-12
期刊：
影响因子：
14
通讯作者：
Muhamed Hadzipasic;Sue Zhang;Zhuoying Huang;Rachel Passaro;Margaret S. Sten;Ganesh M Shankar;Hadi T. Nia
中科院分区：
文献类型：
--
作者：
Muhamed Hadzipasic;Sue Zhang;Zhuoying Huang;Rachel Passaro;Margaret S. Sten;Ganesh M Shankar;Hadi T. Nia
肿瘤是复杂的材料，其物理性质决定了生长和治疗结果。最近的证据表明，时间依赖性的物理特性，如粘弹性，是至关重要的，不同的机械调节癌症的进展和恶性肿瘤，但肿瘤粘弹性的起源和后果知之甚少。在这里，使用宽带AFM为基础的粘弹性光谱（WAVES）结合数学建模，我们探测肿瘤粘弹性的起源。从单个癌细胞到越来越大的癌球体，再到建立的肿瘤，我们描述了动态力学特性的逐步演变，这些动态力学特性创建了建立的肿瘤的纳米流变特征：刚度增加，速率依赖性硬化减少，能量耗散减少。我们按比例解剖粘弹性的这种演变，并显示已建立的肿瘤使用流体-固体相互作用作为机械能耗散的主要机制，而不是流体独立的固有粘弹性。此外，我们证明了球体和已建立的肿瘤中的能量耗散机制与细胞密度呈负相关，并且这种关系强烈依赖于完整的肌动蛋白细胞骨架。这些发现定义了物理肿瘤微环境的紧急和有针对性的特征，有可能更深入地了解肿瘤病理生理学和治疗策略。
Tumors are complex materials whose physical properties dictate growth and treatment outcomes. Recent evidence suggests time-dependent physical properties, such as viscoelasticity, are crucial, distinct mechanical regulators of cancer progression and malignancy, yet the genesis and consequences of tumor viscoelasticity are poorly understood. Here, using Wide-bandwidth AFM-based ViscoElastic Spectroscopy (WAVES) coupled with mathematical modeling, we probe the origins of tumor viscoelasticity. From single carcinoma cells to increasingly sized carcinoma spheroids to established tumors, we describe a stepwise evolution of dynamic mechanical properties that create a nanorheological signature of established tumors: increased stiffness, decreased rate-dependent stiffening, and reduced energy dissipation. We dissect this evolution of viscoelasticity by scale, and show established tumors use fluid-solid interactions as the dominant mechanism of mechanical energy dissipation as opposed to fluid-independent intrinsic viscoelasticity. Additionally, we demonstrate the energy dissipation mechanism in spheroids and established tumors is negatively correlated with the cellular density, and this relationship strongly depends on an intact actin cytoskeleton. These findings define an emergent and targetable signature of the physical tumor microenvironment, with potential for deeper understanding of tumor pathophysiology and treatment strategies.