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dc.contributor.authorBloom, Alexanderen_US
dc.date.accessioned2017-10-05T13:22:37Z
dc.date.issued2017
dc.identifier.urihttps://hdl.handle.net/2144/24109
dc.description.abstractEvery year there are nearly two million new cases of invasive breast cancer worldwide and over 500,000 deaths, the majority from metastatic sites. While cellular changes during tumorigenesis and progression have been studied, our understanding of extracellular matrix remodeling, at the fiber level, by individual and collective cellular cohorts remains limited. Furthermore, recent studies suggest that there is a correlation between the organization of collagen I fibers perpendicular to the tumor and patient survival. However, the underlying mechanism of this alignment remains unknown. The central hypothesis proposed in this dissertation is that breast cancer tumors reorganize collagen I fibers perpendicular to the tumor surface via integrin β1 and matrix metalloproteinases (MMPs). To investigate this hypothesis, we developed a novel in vitro assay that replicates collagen I fiber alignment previously reported in vivo and a new quantitative collagen I fiber orientation algorithm. Our studies using multicellular aggregates, derived from the triple negative breast cancer cell line MDA-MB-231, embedded into collagen I matrices and confocal reflectance microscopy provide novel insights into how the local microenvironment is affected and into local orientation of the collagen I fibers near the spheroid-collagen I interface. These results agree well with our computational studies. Furthermore, the viability of the algorithm is demonstrated using both in silico and in vitro derived images, and shows that this algorithm is more accurate than similar algorithms previously published. Using the developed in vitro assay and computational algorithm it is also demonstrated that knocking down integrin β1 reduces the amount of collagen I aligned perpendicularly to the tumor surface, while inhibiting MMP activity using the broad spectrum MMP inhibitor GM6001 increases the amount of collagen I aligned perpendicularly to the tumor surface at early time points. The work presented here has implications in three-dimensional multicellular assays, accurate fiber orientation analysis, and understanding the role of integrins in matrix reorganization and cancer cell metastasis.en_US
dc.language.isoen_US
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 Internationalen_US
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectMolecular biologyen_US
dc.subjectCollagen Ien_US
dc.subjectAlignmenten_US
dc.subjectBreast canceren_US
dc.subjectExtracellular matrix remodelingen_US
dc.subjectMetastasisen_US
dc.subjectThree dimensional cultureen_US
dc.titleDesign of a three-dimensional in vitro model to elucidate the influence of integrin beta 1 and matrix metalloproteinases in breast cancer remodeling of collagen Ien_US
dc.typeThesis/Dissertationen_US
dc.date.updated2017-08-10T01:13:44Z
dc.description.embargo2019-08-09T00:00:00Z
etd.degree.nameDoctor of Philosophyen_US
etd.degree.leveldoctoralen_US
etd.degree.disciplineMolecular Biology, Cell Biology & Biochemistryen_US
etd.degree.grantorBoston Universityen_US


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Attribution-NonCommercial-NoDerivatives 4.0 International
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivatives 4.0 International