BME PhD Prospectus Defense – Laura Blaha

3:00 pm on Wednesday, August 13, 2014
44 Cummington Mall, Room 203
Title: "A Microfluidic Platform to Examine Competition in Soluble Signaling in the Extravasation Microenvironment"

Joyce Wong, Ph.D. (Chair, Co-Advisor)
Mario Cabodi, Ph.D. (Co-Advisor)
Rhoda Alani, M.D.
Michael Smith, Ph.D.
Joe Tien, Ph.D.

Over 90% of cancer deaths, regardless of tumor origin, are caused by metastasis. Cancer metastasis is the spread of primary tumor cells throughout the body to colonize tumors in new organs. Metastasis begins with primary tumor cells invading underlying stroma and entering the circulatory system. Eventually, circulating tumor cells arrest in the vasculature of a different organ and exit the vessel to establish micrometastases, a process called extravasation. Recent work to understand the mechanisms of metastasis has focused primarily on cell migration within a primary tumor and intravasation into the circulatory system. What remains to be studied are the signals that drive extravasation and, specifically, well-documented trends in organ preference in metastasis.
Chemokine gradients are associated with cell migration in many processes in animal tissues, including the extravasation component of metastasis. Current in vitro studies to investigate chemokine gradients in extravasation have modeled key components of the extravasation microenvironment and observed effects of single chemokines or metastatic niche tissues on cancer cell migration. In vivo, however, cancer cells are exposed to many chemokines simultaneously. Whether it is the collective action of all chemokine gradients at the site of extravasation or a single chemokine that dominates the extravasation process has yet to be addressed and is the primary question driving the proposed study. To answer this question, we propose to design a microfluidic model of extravasation to study migration of cancer cells through a blood vessel wall in response to competing chemokine gradients. Solutions of exogenous chemokines can be tested systematically in pairs to rank chemokines in order of chemotactic response of metastatic cancer cells. Additionally, cells from different metastatic niche tissue can be patterned in the microfluidic model; studying cancer cell extravasation in response to chemokines produced by the niche cells will result in a list of niche tissue ranked in order of preference in extravasation. A comparison of the chemokine expression profiles of highly-ranked metastatic niche cells with the ranked list of chemokines can reveal key chemokines driving organ preference in extravasation. Elucidating the soluble signaling governing extravasation may provide likely targets for drugs aimed at preventing and treating metastasis with the goal of reducing the nearly 8 million cancer deaths each year worldwide.