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Dynamics of 3D carcinoma cell invasion into aligned collagen
Integrative Biology ( IF 1.5 ) Pub Date : 2018-01-17 , DOI: 10.1039/c7ib00152e Arja Ray 1 , Rachel K Morford , Nima Ghaderi , David J Odde , Paolo P Provenzano
Integrative Biology ( IF 1.5 ) Pub Date : 2018-01-17 , DOI: 10.1039/c7ib00152e Arja Ray 1 , Rachel K Morford , Nima Ghaderi , David J Odde , Paolo P Provenzano
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Carcinoma cells frequently expand and invade from a confined lesion, or multicellular clusters, into and through the stroma on the path to metastasis, often with an efficiency dictated by the architecture and composition of the microenvironment. Specifically, in desmoplastic carcinomas such as those of the breast, aligned collagen tracks provide contact guidance cues for directed cancer cell invasion. Yet, the evolving dynamics of this process of invasion remains poorly understood, in part due to difficulties in continuously capturing both spatial and temporal heterogeneity and progression to invasion in experimental systems. Therefore, to study the local invasion process from cell dense clusters into aligned collagen architectures found in solid tumors, we developed a novel engineered 3D invasion platform that integrates an aligned collagen matrix with a cell dense tumor-like plug. Using multiphoton microscopy and quantitative analysis of cell motility, we track the invasion of cancer cells from cell-dense bulk clusters into the pre-aligned 3D matrix, and define the temporal evolution of the advancing invasion fronts over several days. This enables us to identify and probe cell dynamics in key regions of interest: behind, at, and beyond the edge of the invading lesion at distinct time points. Analysis of single cell migration identifies significant spatial heterogeneity in migration behavior between cells in the highly cell-dense region behind the leading edge of the invasion front and cells at and beyond the leading edge. Moreover, temporal variations in motility and directionality are also observed between cells within the cell-dense tumor-like plug and the leading invasive edge as its boundary extends into the anisotropic collagen over time. Furthermore, experimental results combined with mathematical modeling demonstrate that in addition to contact guidance, physical crowding of cells is a key regulating factor orchestrating variability in single cell migration during invasion into anisotropic ECM. Thus, our novel platform enables us to capture spatio-temporal dynamics of cell behavior behind, at, and beyond the invasive front and reveals heterogeneous, local interactions that lead to the emergence and maintenance of the advancing front.
中文翻译：
3D 癌细胞侵入排列胶原蛋白的动力学
癌细胞经常从局限性病变或多细胞簇扩展并侵入，进入并穿过间质，直至转移，其效率通常由微环境的结构和组成决定。具体来说，在诸如乳腺癌之类的促纤维增生性癌中，对齐的胶原轨迹为定向癌细胞侵袭提供了接触引导线索。然而，这种入侵过程的演变动态仍然知之甚少，部分原因是在实验系统中持续捕获空间和时间异质性以及入侵进展的困难。因此，为了研究实体瘤中从细胞密集簇到排列的胶原蛋白结构的局部侵袭过程，我们开发了一种新颖的工程3D侵袭平台，该平台将排列的胶原蛋白基质与细胞密集的肿瘤样栓整合在一起。使用多光子显微镜和细胞运动的定量分析，我们跟踪癌细胞从细胞密集的块状簇侵入预先对齐的 3D 矩阵，并定义了几天内前进的侵入前沿的时间演变。这使我们能够识别和探测关键感兴趣区域的细胞动态：在不同时间点入侵病变的后面、边缘处和边缘之外。单细胞迁移分析发现，入侵前沿前沿后面的高度细胞密集区域的细胞与前沿处和前沿之外的细胞之间的迁移行为存在显着的空间异质性。此外，随着时间的推移，随着其边界延伸到各向异性胶原中，细胞密集的肿瘤样栓内的细胞和主要的侵入边缘之间也观察到运动性和方向性的时间变化。 此外，实验结果与数学模型相结合表明，除了接触引导之外，细胞的物理拥挤是在侵入各向异性 ECM 期间协调单细胞迁移变异性的关键调节因素。因此，我们的新颖平台使我们能够捕获侵入前沿后面、处和之外的细胞行为的时空动态，并揭示导致前进前沿出现和维持的异质局部相互作用。
更新日期：2018-01-17
中文翻译：
3D 癌细胞侵入排列胶原蛋白的动力学
癌细胞经常从局限性病变或多细胞簇扩展并侵入，进入并穿过间质，直至转移，其效率通常由微环境的结构和组成决定。具体来说，在诸如乳腺癌之类的促纤维增生性癌中，对齐的胶原轨迹为定向癌细胞侵袭提供了接触引导线索。然而，这种入侵过程的演变动态仍然知之甚少，部分原因是在实验系统中持续捕获空间和时间异质性以及入侵进展的困难。因此，为了研究实体瘤中从细胞密集簇到排列的胶原蛋白结构的局部侵袭过程，我们开发了一种新颖的工程3D侵袭平台，该平台将排列的胶原蛋白基质与细胞密集的肿瘤样栓整合在一起。使用多光子显微镜和细胞运动的定量分析，我们跟踪癌细胞从细胞密集的块状簇侵入预先对齐的 3D 矩阵，并定义了几天内前进的侵入前沿的时间演变。这使我们能够识别和探测关键感兴趣区域的细胞动态：在不同时间点入侵病变的后面、边缘处和边缘之外。单细胞迁移分析发现，入侵前沿前沿后面的高度细胞密集区域的细胞与前沿处和前沿之外的细胞之间的迁移行为存在显着的空间异质性。此外，随着时间的推移，随着其边界延伸到各向异性胶原中，细胞密集的肿瘤样栓内的细胞和主要的侵入边缘之间也观察到运动性和方向性的时间变化。 此外，实验结果与数学模型相结合表明，除了接触引导之外，细胞的物理拥挤是在侵入各向异性 ECM 期间协调单细胞迁移变异性的关键调节因素。因此，我们的新颖平台使我们能够捕获侵入前沿后面、处和之外的细胞行为的时空动态，并揭示导致前进前沿出现和维持的异质局部相互作用。
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