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Metastasis is the leading cause of death among cancer patients. The metastatic cascade, during which cancer cells from the primary tumor reach a distant organ and form multiple secondary tumors, consists of a series of events starting with cancer cells invasion through the surrounding tissue of the primary tumor. Invading cells may perform proteolytic degradation of the surrounding extracellular matrix (ECM) and directed migration in order to disseminate through the tissue. Both of the mentioned processes are profoundly affected by several parameters originating from the tumor microenvironment (extrinsic) and tumor cells themselves (intrinsic). However, due to the complexity of the invasion process and heterogeneity of the tumor tissue, the exact effect of many of these parameters are yet to be elucidated. ECM proteolysis is widely performed by cancer cells to facilitate the invasion process through the dense and highly cross-linked tumor tissue. It has been shown in vivo that the proteolytic activity of the cancer cells correlates with the cross-linking level of their surrounding ECM. Therefore, the first part of this thesis seeks to understand how ECM cross-linking regulates cancer cells proteolytic activity. This chapter first quantitatively characterizes the correlation between ECM cross-linking and the dynamics of cancer cells proteolytic activity and then identifies ß1-integrin subunit as a master regulator of this process. Once cancer cells degrade their immediate ECM, they directionally migrate through it. Bundles of aligned collagen fibers and gradients of soluble growth factors are two well-known cues of directed migration that are abundantly present in tumor tissues stimulating contact guidance and chemotaxis, respectively. While such cues direct the cells towards a specific direction, they are also known to stimulate cell cycle progression. Moreover, due to the complexity of the tumor tissue, cells may be exposed to both cues simultaneously, and this co-stimulation may happen in the same or different directions. Hence, in the next two chapters of this thesis, the effect of cell cycle progression and contact guidance-chemotaxis dual-cue environments on directional migration of invading cells are assessed. First, we show that cell cycle progression affects contact guidance and not random motility of the cells. Next, we show how exposure of cancer cells to contact guidance-chemotaxis dual-cue environments can improve distinctive aspects of cancer invasion depending on the spatial conformation of the two cues. In this dissertation, we strive to achieve the defined milestones by developing novel mathematical and experimental models of cancer invasion as well as utilizing fluorescent time-lapse microscopy and automated image and signal processing techniques. The results of this study improve our knowledge about the role of the studied extrinsic and intrinsic cues in cancer invasion. / Bioengineering / Accompanied by fourteen .avi files.

Spatial information about invasive species abundance is critical for estimating impact and understanding risk to ecosystems and economies. Unfortunately, at landscape and regional scales, most distribution datasets provide limited information about abundance. However, national and regional invasive plant occurrence datasets are increasingly available and spatially extensive. We aim to test whether the frequency of these point occurrences can be used as a proxy for abundance of invasive plants. We compiled both occurrence and abundance data for nine regionally important invasive plants in the northeast US using a combination of herbarium records, surveys of expert knowledge, and various invasive species spatial databases. We integrated all available abundance information based on infested area, percent cover, or qualitative descriptions into abundance rankings ranging from 0 (absent) to 4 (highly abundant). Within equal area grid cells of 800 m, we counted numbers of occurrence points and used an ordinal regression to test whether higher numbers of occurrence points were positively correlated with abundance rankings. We compiled a total 49,341 occurrence points in 18,533 cells, of which 12,183 points (25%) within 4,278 cells (32%) had associated abundance information. In six of nine study species we found slight but significant positive overall relationships between abundance rank and occurrence frequency at high abundance ranks. However, at low abundance rankings the relationship tended to be negative and the magnitude of the overall difference in occurrence frequency was too small to be relevant to management. My results suggest that currently available occurrence datasets are unlikely to serve as effective proxies for abundance, and models derived from invasive plant occurrence datasets should not be interpreted as indicative of plant abundance and associated impact. Increased efforts to collect and report invasive species abundance information, and/or higher densities of occurrence points in heavily infested areas are strongly needed for regional scale assessments of potential abundance and associated impact.

Blue Catfish were introduced in the tidal tributaries of the Chesapeake Bay in the 1970s and 1980s to establish new fisheries during a time period when many fisheries were in decline due to pollution, habitat alteration, disease, overfishing, and environmental catastrophes. Having expanded their range to most Bay tributaries, the species has drawn concern from many stakeholders and scientists for its effects on at-risk and economically important native and naturalized species. My study focused on understanding the dynamics of this species based on multiple long-term monitoring data and evaluating potential management strategies to meet stakeholder needs. I sought to understand how is growth variability was partitioned over time and space, how Blue Catfish populations changed from 1994 to 2016, and how predation on native species and fishery-based performance measures may respond to management intervention. As Blue Catfish length-at-age is exceptionally variable in Virginia tributaries of the Chesapeake Bay, I evaluated the variability in growth using candidate non-linear mixed effects models that described variability in growth over time and space. Linear trend tests supported declines in growth over time within river systems, but did not support the presence of synchronous growth responses among river systems. To better understand population dynamics of Blue Catfish in the Chesapeake Bay watershed, I developed a statistical catch-at-length model for the James River to estimate population size, instantaneous fishing mortality, and size structure over time. The statistical catch-at-length model estimated that Blue Catfish abundance increased slowly and peaked in the mid-2000s before undergoing a recent decline. The model estimated a large spike in abundance due to an estimated large recruitment event in 2011, but may be an artifact of missing data in 2012 in both relative abundance indices examined. The newly developed statistical catch-at-length model provides most detailed information on population dynamics of Blue Catfish in the James River and can be expanded and updated as new data become available. Based on results of the statistical catch-at-length model, I examined population responses to unregulated, maximum length limit (60 cm), and harvest slot limit regulations (harvest allowed 25 –60 cm) in a management strategy evaluation framework. The management strategy evaluation supported that the James River Blue Catfish population could be reduced with increased harvest, but trophy-size fish would decline. Consequently, fishery managers tasked with invasive species management must consider this tradeoff of fishery economic benefits and predation on native populations, especially those prey in which population sizes are unknown. / Doctor of Philosophy / Blue Catfish are non-native to the Chesapeake Bay watershed, but were stocked in the 1970s and 1980s to provide fishing opportunities to the region. Unknowingly, Blue Catfish expanded downstream and beyond the boundaries of the rivers to which they were originally stocked and now exist in extremely dense populations in places. This expansion in population size and distribution has generated concern for the health of the Chesapeake Bay and calls for population control. I wanted to learn more about Blue Catfish in Virginia, specifically Blue Catfish growth rates, population dynamics, and how they might respond to control efforts. I examined Blue Catfish growth rates and found growth rates differed over time and across river systems. Blue Catfish tended to grow more slowly over time as their populations matured. As growth rates declined, population size increased with maximum population sizes in the late 2000s in the James River with a subsequent decline in abundance. Many invasive species exhibit this sort of phenomenon, where population sizes increase and reach a maximum before declining. Finally, I looked at Blue Catfish responses to different fishing regulations and harvest levels, finding that increased harvest could help control Blue Catfish population sizes. However, Blue Catfish management objectives are in conflict as regulations that limit predation of native species of interest also reduce the proportion of large fish in populations. Blue Catfish management will require stakeholder-driven approaches to ensure buy-in and reduce user conflicts.