A6: Cell & Molecular Mechanobiology II

QUANTITATIVE ASSESSMENT OF CIRCULATING TUMOR CELL EXTRAVASATION IN A 3D MICROVASCULAR NETWORK SYSTEM

Jiho Song1,2, Bee Luan Khoo3, Giulia Adriani3, Soo Chin Lee4,5, Chwee Teck Lim6, Roger D. Kamm2

1Singapore-MIT Alliance for Research and Technology, Singapore;
2Massachusetts Institute of Technology, USA;
3Singapore-MIT Alliance for Research and Technology (SMART);
4National University Hospital, Singapore;
5National University Cancer Institute, Singapore;
6National University of Singapore

In the past two decades, several studies have shown that circulating tumor cells (CTCs) play a major role in cancer metastasis. Extravasation, the process by which CTCs escape from the vasculature in a remote tissue, is a critical step in the metastatic cascade.  This involves tumor cell arrest on the endothelium, formation of dynamic contacts, tumor cell transendothelial migration and subsequent invasion into the surrounding tissue of secondary organs. Although extravasation is a recognized step in the metastatic cascade, the precise cellular interactions and molecular alterations associated with extravasation are poorly understood, especially in the case of patient-derived CTCs. Recent advances in microfabrication technologies and advanced biomaterials have allowed for the development of in vitro platforms that recapitulate more physiologically relevant cellular components and functions. In this work, 3D vascular networks with effective lumen diameters of 10 to 100 µm are formed in the central region of a microfluidic device measuring 1x3x20 mm. We introduced patient-derived CTCs previously cultured in laser-ablated microwells for 14 days by perfusing them into the microvasculature networks and observing them by time-lapse microscopy. In this way, CTCs could be visualized migrating across the endothelium in a precisely controlled and physiologically relevant microenvironment, providing important insights into extravasation mechanisms. We have also tested fluorescently tagged breast and lung cancer cell lines (MDA-MB-231 and A549) and observed their transmigration through the vessel walls in real time. Observations of the ability of CTCs to extravasate could be used to assess the risk of a particular patient to form metastases at different stages in their disease. Furthermore, this approach may be useful for drug screening to assess the success of potential therapeutic treatments.
 

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