Date of Award

2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Chemical and Biomolecular Engineering

First Advisor

Christopher S. Chen

Abstract

Cell migration is an essential and highly regulated process. Cells migrate to vascularize tissues, to form tissue, and to respond to inflammation. Unfortunately, cell migration is also involved in numerous pathological conditions such as in invasive tumors. Cells can migrate as individual cells or as collective groups of cells. Particularly important in cell migration is the collective migration of cells as it is a hallmark of tissue remodeling events during embryonic morphogenesis, wound repair, and cancer invasion. Perhaps, angiogenesis is one of the most crucial collective migration processes as it is involved in multiple physiological and pathological conditions such as formation of vasculature, wound healing, cancer progression and metastasis. During angiogenesis, endothelial cells migrate collectively from existing vasculature in response to a complex biochemical and mechanical cues to form multicellular structures that eventually develop into new functional blood vessels. Angiogenesis is also a highly dynamic process where multiple cells rearrange and coordinate within a sprout. Such dynamic rearrangement requires different cytoskeletal regulators such as Rho GTPases proteins (RhoA, Rac, and Cdc42). Although the roles of Rho GTPase proteins have been well characterized in 2D cell migration, little is known about their contributions in angiogenic morphogenesis. Here, we engineered a 3D biomimetic microfluidic-based device, called AngioChip, where endothelial cells are induced to migrate collectively from a pre-formed biomimetic cylindrical blood vessel into a 3D interstitial collagen matrix. The sprouts in our AngioChip demonstrate in vivo-like morphogenetic features such as formation of tip-stalk cells, lumen formation, filopodial-like protrusions in leading tip cells, and formation of perfusable neovessels. Using this system, we examine the roles of Cdc42 to regulate many aspects of angiogenic morphogenesis. We find that disturbing Cdc42 activity reduces formation of branches, migration speed, and collective migration. Additionally, Cdc42 also negatively regulate filopodia formation. We also develop the AngioChip into a pancreatic ductal adenocarcinoma (PDAC) on a chip to investigate the interactions between pancreatic cancer cells and blood vessels. Vascular invasion, where PDAC cells invaded towards the vasculature during tumor progression, is a hallmark of metastatic PDAC. Nevertheless, how pancreatic tumor cells interact with the blood vessels remains largely unknown. Using our PDAC-on-a-chip, we reveal a striking observation where PDAC cells invade and de-endothelialize the blood vessels. This de-endothelialization process leads to vascular replacement in the blood vessels and is mediated by proliferation of PDAC through Nodal/Activin-ALK7 signaling.

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