Graduate Thesis Or Dissertation


Mechanics Controls Collective Cancer Invasion Public Deposited

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  • Cancer cell migration in three-dimensional extracellular matrix is a major cause of death for cancer patients. Although extensive studies have elucidated detailed mechanism of single cell 3D invasion and cell-ECM interaction, 3D collective cancer invasion is still poorly understood. 3D collective migration models have unveiled unexpected degrees of diversity and adoption in migration and have an advantage over the 2D collective models by mimicking in vivo conditions. To probe 3D collective cancer migration, diverse in vitro methods have been designed to explore the physical factors that regulate the multicellular processes. The role of ECM geometry and microstructure has been poorly understood in 3D collective cancer migration. To capture collective cancer invasion, we developed a novel 3D invasion assay, Diskoid In Geometrically Micropatterned ECM (DIGME). DIGME allows us to independently control the shape of tumor organoids, microstructure, spatial heterogeneity of the extracellular matrix and fiber alignment of collagen –based ECM all at the same time. Using fluorescence and confocal microscopy, we probe the invasion front of different geometry and morphology phenotypes. We conclude that DIGME provides a simple yet powerful tool to probe the 3D dynamics of tissue orgnoids in physically patterned microenvironments. To probe the cooperativity of force generation in the collective invasion of breast cancer cells, we conduct experiments using 3D in vitro tumor models and develop a phenomenological model. In our model, cell–cell communication is characterized by a single parameter that quantifies the correlation length of cellular migration cycles. We devise a stochastic reconstruction method to generate realizations of cell colonies with specific contraction phase correlation functions and correlation length a. We find that as a increases, the characteristic size of regions containing cells with similar contraction phases grows. For small a values, the large fluctuations in individual cell contraction phases smooth out the temporal fluctuations in the time-dependent deformation field in the ECM. For large a values, the periodicity of an individual cell contraction cycle is clearly manifested in the temporal variation of the overall deformation field in the ECM. Through quantitative comparisons of the simulated and experimentally measured deformation fields, we find that the correlation length for collective force generation in the breast cancer diskoid in geometrically micropatterned ECM (DIGME) system is 𝑎 ≈ 25𝜇𝑚, which is roughly twice the linear size of a single cell. One possible mechanism for this intermediate cell correlation length is the fiber-mediated stress propagation in the 3D ECM network in the DIGME system. We conclude that the geometrical properties of the ECM and microstructure play a role in regulating the 3D collective cancer invasion.
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