(6at) The Role of Topographical Cues in Cancer Cell Migration and Metastasis

My research program will focus on: (1) studying how and why physical forces, especially those related to the architecture or topography of the microenvironment in distinct tissues, influence the spread and formation of metastatic cancers; and (2) developing therapeutics that target interactions between disseminated tumor cells and the physical microenvironment to inhibit the progression of metastatic cancers.

Metastasis describes the process whereby cancer cells move from a primary tumor to establish lesions in distinct secondary organs. Experiments in animal models suggest that thousands to millions of tumor cells per gram of tumor can be shed into the circulatory system per day, but that very few survive to form metastases. If this large quantity of cells enters the circulatory system, perhaps even before the detection of a primary tumor, why do some cancer cells survive and grow into metastases? Furthermore, if dissemination of cells occurs early in the lifespan of a tumor, how can we design and execute treatment methods to check the growth of disseminated tumor cells? It is likely that many rate-limiting steps in metastasis occur early in colonization, before secondary tumors are detectable in patients or in murine models. These patterns of early dissemination are particularly common in breast, esophageal, and renal cell cancers, while microenvironmental preconditioning from the primary tumor may be more important in the metastasis of prostrate, colorectal, and pancreatic cancers.

My research program will initially focus on how topographical cues that disseminating tumor cells receive from the architecture of the microenvironment in distinct organs modulate cell arrest and extravasation. Specifically, I will study the mechanisms by which disseminating cancer cells arrest, survive, and extravasate in biomimetic microfluidic devices and in blood vessels of varying topographical organization in the zebrafish hematopoietic niche and brain. Microfluidic devices will be engineered to recapitulate key physical features of vascular topography found in vivo. Key findings will be confirmed in intravital experiments in the larval Danio rerio (zebrafish), an optically transparent and relatively inexpensive model organism. Cytokines associated with tumor progression as observed in murine and human studies are conserved in the zebrafish, and ~70% of human genes have at least one zebrafish orthologue. My postdoctoral work elucidated mechanisms leading to organotropism (the clinical observation that different types of primary cancers preferentially metastasize to different organs) of human and murine brain- and bone marrow-seeking breast cancer cells in a larval zebrafish xenograft model. In this model, brain-targeting cells colonized the brain at greater rates than bone marrow-targeting cells. Bone marrow-targeting cells were more likely to extravasate in the caudal vein plexus (CVP), a hematopoietic niche in the larval zebrafish tail that is analogous to mammalian bone marrow. Functional and mechanistic experiments in microfluidic devices and zebrafish will identify druggable targets that can be exploited during cancer cell dissemination, the exploration of which will form the basis for future grant applications.

My long-term career goals are to leverage an improved understanding of the mechanisms of early cancer cell dissemination, extravasation, and colonization to develop treatments to prevent the growth of metastatic cancer or force metastatic cells into dormancy. In analogy to the role of topography in cancer cell migration, I hypothesize that immune cell access to disseminated cancer cells could depend on the physical environment (ECM organization, outward fluid flow from blood vessels, etc.) around disseminated cells, and that reduced access of immune cells to dormant tumor cells slows their clearance by immune cells. Understanding these forces may help develop drugs and/or immunotherapy strategies that prime the immune system to recognize disseminated cells before they can grow into large metastases. Therefore, future research projects will also assess how microenvironmental topographical cues influence the phenotype of immune cells in various organs.

Teaching Interests:

My teaching goals are to prepare students for a wide range of chemical engineering and biotechnology careers by supporting critical thinking, integration of new information into existing frameworks, and use of available tools to solve real-life problems. I am interested in teaching undergraduate and graduate courses in fluid mechanics, transport, separations, biomechanics, and imaging theory and methods, as well as seminars or graduate courses in microfluidic techniques and technologies. I am also willing to teach online courses. I have had teaching experience as a graduate assistant in Chemical and Biomolecular Engineering Transport I (undergraduate course) and a NanoBioTechnology lab course (graduate course). I have also completed a course on pedagogy sponsored by the National Institutes of Health (NIH) that is designed to prepare scientists for instruction in STEM fields, and I have served as a course instructor and mentor for summer students at the NIH.