Two channel compartmentalized microfluidic chip for real time monitoring of the metastatic cascade

TL;DR

This study introduces a novel two-channel microfluidic chip that mimics key steps of cancer metastasis in vitro, allowing detailed analysis of tumor cell intravasation, extravasation, and invasion under controlled conditions.

Contribution

The paper presents a new microfluidic device capable of replicating the metastatic cascade, enabling systematic study of cancer cell behavior and interactions with the vascular environment.

Findings

Cancer cell intravasation rate of 8 cells/day

Extravasation rate of 4 cells/day with TNF-a stimulation

Invasion rate of 12 cells/day upon TNF-a stimulation

Abstract

Metastases are the primary cause of death in cancer patients. Small animal models are helping in dissecting some of key features in the metastatic cascade. Yet, tools for systematically analyze the contribution of blood flow, vascular permeability, inflammation, tissue architecture, and biochemical stimuli are missing. In this work, a microfluidic chip is designed and tested to replicate in vitro key steps in the metastatic cascade. It comprises two channels, resting on the same plane, connected via an array of rounded pillars to form a permeable micro-membrane. One channel acts as a vascular compartment and is coated by a fully confluent monolayer of endothelial cells, whereas the other channel is filled with a mixture of matrigel and breast cancer cells (MDA-MB-231) and reproduces the malignant tissue. The vascular permeability can be finely modulated by inducing pro-inflammatory conditions in the tissue compartment, which transiently opens up the tight junctions of endothelial cells. Fresh medium flowing continuously in the vascular compartment is sufficient to induce cancer cell intravasation at rates of 8 cells/day with an average velocity of 0.5 um/min. On the other hand, the vascular adhesion and extravasation of circulating cancer cells require TNF-a stimulation. Extravasation occurs at lower rates with 4 cells/day and an average velocity of 0.1 um/min. Finally, the same chip is completely filled with matrigel and the migration of cancer cells from one channel to the other is monitored over a region of about 400 um. Invasion rates of 12 cells/day are documented upon TNF-a stimulation. This work demonstrates that the proposed compartmentalized microfluidic chip can efficiently replicate in vitro, under controlled biophysical and biochemical conditions, the multiple key steps in the cancer metastatic cascade.