Venugopalan Gautham, Camarillo David B, Webster Kevin D, Reber Clay D, Sethian James A, Weaver Valerie M, Fletcher Daniel A, El-Samad Hana, Rycroft Chris H
Department of Bioengineering and Biophysics Program, University of California, Berkeley, California, United States of America.
Department of Bioengineering, Stanford University, Stanford, California, United States of America; Department of Biochemistry & Biophysics, University of California San Francisco, San Francisco, California, United States of America.
PLoS One. 2014 Aug 11;9(8):e101955. doi: 10.1371/journal.pone.0101955. eCollection 2014.
Cell-matrix and cell-cell mechanosensing are important in many cellular processes, particularly for epithelial cells. A crucial question, which remains unexplored, is how the mechanical microenvironment is altered as a result of changes to multicellular tissue structure during cancer progression. In this study, we investigated the influence of the multicellular tissue architecture on mechanical properties of the epithelial component of the mammary acinus. Using creep compression tests on multicellular breast epithelial structures, we found that pre-malignant acini with no lumen (MCF10AT) were significantly stiffer than normal hollow acini (MCF10A) by 60%. This difference depended on structural changes in the pre-malignant acini, as neither single cells nor normal multicellular acini tested before lumen formation exhibited these differences. To understand these differences, we simulated the deformation of the acini with different multicellular architectures and calculated their mechanical properties; our results suggest that lumen filling alone can explain the experimentally observed stiffness increase. We also simulated a single contracting cell in different multicellular architectures and found that lumen filling led to a 20% increase in the "perceived stiffness" of a single contracting cell independent of any changes to matrix mechanics. Our results suggest that lumen filling in carcinogenesis alters the mechanical microenvironment in multicellular epithelial structures, a phenotype that may cause downstream disruptions to mechanosensing.
细胞与基质以及细胞与细胞之间的机械传感在许多细胞过程中都很重要，尤其是对于上皮细胞而言。一个尚未得到探索的关键问题是，在癌症进展过程中，多细胞组织结构的变化会如何导致机械微环境发生改变。在本研究中，我们调查了多细胞组织结构对乳腺腺泡上皮成分机械性能的影响。通过对多细胞乳腺上皮结构进行蠕变压缩试验，我们发现无管腔的癌前腺泡（MCF10AT）比正常的中空腺泡（MCF10A）硬度显著高60%。这种差异取决于癌前腺泡的结构变化,因为在管腔形成之前测试的单细胞或正常多细胞腺泡均未表现出这些差异。为了理解这些差异，我们模拟了具有不同多细胞结构的腺泡变形，并计算了它们的机械性能；我们的结果表明，仅管腔填充就能解释实验观察到的硬度增加。我们还模拟了在不同多细胞结构中的单个收缩细胞，发现管腔填充导致单个收缩细胞的“感知硬度”增加20%，而与基质力学的任何变化无关。我们的结果表明，致癌过程中的管腔填充会改变多细胞上皮结构中的机械微环境，这一表型可能会导致下游机械传感功能的破坏。
