Micromechanical remodeling of the extracellular matrix by invading tumors: anisotropy and heterogeneity
Micromechanical remodeling of the extracellular matrix by invading tumors: anisotropy and heterogeneity
复制标题
侵袭肿瘤对细胞外基质的微机械重塑：各向异性和异质性
作者：
Naylor, Austin;Zheng, Yu;Jiao, Yang;Sun, Bo
改变的组织力学是侵袭性实体瘤的重要标志。虽然已经通过测量肿瘤周围细胞外基质（ECM）的体积流变学对该现象进行了广泛的研究，但对细胞尺度的微机械重塑仍然知之甚少。通过结合全息光镊和共聚焦显微镜在体外肿瘤模型，我们表明，周围的入侵肿瘤的胶原ECM的微观力学表现出方向各向异性，空间异质性和显着的变化，随着肿瘤的侵入时间。为了测试ECM微机械重塑的细胞机制，我们构建了一个简单的计算模型，并用实验验证其预测。我们发现，集体力产生的肿瘤硬化的ECM，并导致各向异性的局部力学，使延伸方向比压缩方向更刚性。细胞分泌的基质金属蛋白酶降解ECM使ECM软化，并且来自单个播散细胞的主动牵引力使基质恢复。总之，这些结果确定了合理的生物物理机制，负责重塑ECM微观力学周围的入侵肿瘤。
Altered tissue mechanics is an important signature of invasive solid tumors. While the phenomena have been extensively studied by measuring the bulk rheology of the extracellular matrix (ECM) surrounding tumors, micromechanical remodeling at the cellular scale remains poorly understood. By combining holographic optical tweezers and confocal microscopy on in vitro tumor models, we show that the micromechanics of collagen ECM surrounding an invading tumor demonstrate directional anisotropy, spatial heterogeneity and significant variations in time as tumors invade. To test the cellular mechanisms of ECM micromechanical remodeling, we construct a simple computational model and verify its predictions with experiments. We find that collective force generation of a tumor stiffens the ECM and leads to anisotropic local mechanics such that the extension direction is more rigid than the compression direction. ECM degradation by cell-secreted matrix metalloproteinase softens the ECM, and active traction forces from individual disseminated cells re-stiffen the matrix. Together, these results identify plausible biophysical mechanisms responsible for the remodeled ECM micromechanics surrounding an invading tumor.