Nagle Irène, Tavasso Margherita, Bordoloi Ankur D, Muntz Iain A A, Koenderink Gijsje H, Boukany Pouyan E
Department of Bionanoscience, Kavli Institute of Nanoscience, Delft University of Technology, Delft, the Netherlands.
Department of Chemical Engineering, Delft University of Technology, Delft, the Netherlands.
Acta Biomater. 2025 Aug 26. doi: 10.1016/j.actbio.2025.08.036.
Collagen networks form the structural backbone of the extracellular matrix in both healthy and cancerous tissues, exhibiting nonlinear mechanical properties that crucially regulate tissue mechanics and cell behavior. Here, we investigate how the presence of invasive breast cancer cells (MDA-MB-231) influences the polymerization kinetics and mechanics of collagen networks using bulk shear rheology and rheo-confocal microscopy. We show that embedded cancer cells delay the onset of collagen polymerization due to volume exclusion effects. During polymerization, the cells (at 4% volume fraction) cause an unexpected time-dependent softening of the network. We show that this softening effect arises from active remodeling via adhesion and contractility rather than from proteolytic degradation. At higher cell volume fractions, the dominant effect of the cells shifts to volume exclusion, causing a two-fold reduction of network stiffness. Additionally, we demonstrate that cancer cells suppress the characteristic stress-stiffening response of collagen. This effect (partially) disappears when cell adhesion and contractility are inhibited, and it is absent when the cells are replaced by passive hydrogel particles. These findings provide new insights into how active inclusions modify the mechanics of fibrous networks, contributing to a better understanding of the role of cells in the mechanics of healthy and diseased tissues like invasive tumors. STATEMENT OF SIGNIFICANCE: Understanding how cells influence tissue mechanics is crucial to unravel disease progression. While fibroblasts are known to stiffen tissues, the role of invasive cancer cells is less clear. Using collagen-based tissue models, we reveal that cancer cells unexpectedly soften the collagen matrix and disrupt its stress-stiffening response. By comparing active cells to passive particles and selectively blocking cell functions, we show that volume exclusion, adhesion, and contractility each play distinct roles in shaping tissue mechanics. This work sheds light on the physical impact of cancer cells on their environment, advancing our understanding on how cells dynamically alter the mechanical properties of tissues.
胶原蛋白网络构成了健康组织和癌组织细胞外基质的结构骨架，呈现出非线性力学特性，对组织力学和细胞行为起着至关重要的调节作用。在此，我们利用体剪切流变学和流变共聚焦显微镜研究侵袭性乳腺癌细胞（MDA-MB-231）的存在如何影响胶原蛋白网络的聚合动力学和力学性能。我们发现，由于体积排阻效应，嵌入的癌细胞会延迟胶原蛋白聚合的起始。在聚合过程中，细胞（体积分数为4%）会导致网络出现意想不到的随时间变化的软化现象。我们表明，这种软化效应源于通过黏附力和收缩性进行的主动重塑，而非蛋白水解降解。在更高的细胞体积分数下，细胞的主要作用转变为体积排阻，导致网络刚度降低两倍。此外，我们证明癌细胞会抑制胶原蛋白的特征性应力硬化响应。当细胞黏附力和收缩性受到抑制时，这种效应（部分）消失；当细胞被被动水凝胶颗粒取代时，则不存在这种效应。这些发现为活性内含物如何改变纤维网络力学性能提供了新的见解，有助于更好地理解细胞在侵袭性肿瘤等健康和患病组织力学中的作用。重要性声明：了解细胞如何影响组织力学对于揭示疾病进展至关重要。虽然已知成纤维细胞会使组织变硬，但侵袭性癌细胞的作用尚不清楚。利用基于胶原蛋白的组织模型，我们发现癌细胞意外地使胶原蛋白基质软化并破坏其应力硬化响应。通过将活性细胞与被动颗粒进行比较，并选择性地阻断细胞功能，我们表明体积排阻、黏附力和收缩性在塑造组织力学方面各自发挥着不同的作用。这项工作揭示了癌细胞对其环境的物理影响，增进了我们对细胞如何动态改变组织力学性能的理解。
