Effects of three-dimensional extracellular matrix properties on tumor cell behavior

Thesis ()--Boston UniversityPLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.Cancer is a devastating disease that claims millions of lives each year. It has long been recognized that solid tumors are usually much stiffer than normal tissues. While it is well-established that extracellular matrix (ECM) properties affect many aspects of cell behaviour, the implications of altered matrix properties in cancer progression has not been investigated in a systematic, quantitative fashion. The question of how cell-ECM interactions drive cancer, especially in in vivo -like 3D conditions, is of great interest since tumor cells are closely interfacing with the ECM during metastasis. The central hypothesis of this work is that 3D ECM properties affect motility and matrix remodeling, two key components of invasion. This was explored in four studies. First, we developed a force-based simulation of the effect of proteolytic matrix degradation on 3D cell migration and found that peak motility is achieved at intermediate ECM ligand and matrix metalloproteinase (MMP) concentrations, with a linear relationship between ligand and MMPs yielding physiologically compelling results. Second, we used confocal reflectance microscopy to monitor remodeling behavior of two prostate cancer cell lines, LNCaP and DU-145, seeded in 3D matrices of varying collagen content. While both cell types increased the fraction of fibrils in the lowest density collagen gels, in higher density gels, the more invasive cells modified gels to achieve much higher fibril fractions. This difference was found to be due in part to higher MMP production in the more invasive DU-145 cell line. A 3D lattice-based Monte Carlo model was also developed that recreated this matrix remodeling experiment, explicitly accounting for both cellular and matrix properties, and confirmed the finding that more invasive cells more aggressively increase fibril fractions of their substrates. Finally, the dispersal of multicellular tumoroids was found to be dependent on matrix properties. Clusters of DU-145 cells dispersed most readily on 2D substrates and at intermediate collagen concentration in 3D. In summary, we found that 3D ECM properties can dictate how cancer cells migrate and reorganize their microenvironment. This work has major implications for understanding the clinically significant process of metastasis.2031-01-0