Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, India.
Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, India.
Biophys J. 2018 Feb 6;114(3):650-662. doi: 10.1016/j.bpj.2017.11.3777.
Invadopodia are micron-sized invasive structures that mediate extracellular matrix (ECM) degradation through a combination of membrane-bound and soluble matrix metalloproteinases (MMPs). However, how such localized degradation is converted into pores big enough for cancer cells to invade, and the relative contributions of membrane-bound versus soluble MMPs to this process remain unclear. In this article, we address these questions by combining experiments and simulations. We show that in MDA-MB-231 cells, an increase in ECM density enhances invadopodia-mediated ECM degradation and decreases inter-invadopodia spacing. ECM degradation is mostly mediated by soluble MMPs, which are activated by membrane-bound MT1-MMP. We present a computational model of invadopodia-mediated ECM degradation, which recapitulates the above observations and identifies MMP secretion rate as an important regulator of invadopodia stability. Simulations with multiple invadopodia suggest that inter-invadopodia spacing and MMP secretion rate collectively dictate the size of the degraded zones. Taken together, our results suggest that for creating pores conducive for cancer invasion, cells must tune inter-invadopodia spacing and MMP secretion rate in an ECM density-dependent manner, thereby striking a balance between invadopodia penetration and ECM degradation.
侵袭伪足是微米大小的侵袭结构，通过膜结合和可溶性基质金属蛋白酶（MMPs）的组合来介导细胞外基质（ECM）的降解。然而，这种局部降解如何转化为足够大的孔，使癌细胞能够侵袭，以及膜结合型 MMPs 和可溶性 MMPs 对这一过程的相对贡献仍不清楚。在本文中，我们通过结合实验和模拟来解决这些问题。我们表明，在 MDA-MB-231 细胞中，ECM 密度的增加增强了侵袭伪足介导的 ECM 降解，并减少了侵袭伪足之间的间隔。ECM 降解主要由可溶性 MMPs 介导，这些 MMPs 被膜结合型 MT1-MMP 激活。我们提出了一个侵袭伪足介导的 ECM 降解的计算模型，该模型再现了上述观察结果，并确定了 MMP 分泌率是侵袭伪足稳定性的一个重要调节因子。多个侵袭伪足的模拟表明，侵袭伪足之间的间隔和 MMP 分泌率共同决定了降解区的大小。总之，我们的研究结果表明，为了创造有利于癌症侵袭的孔，细胞必须以 ECM 密度依赖性的方式调节侵袭伪足之间的间隔和 MMP 分泌率，从而在侵袭伪足的穿透和 ECM 的降解之间取得平衡。
