An optofluidic constriction chip for monitoring metastatic potential and drug response of cancer cells

Abstract

Cellular mechanical properties constitute good markers to characterize tumor cells, to study cell population heterogeneity and to highlight the effect of drug treatments. In this work, we describe the fabrication and validation of an integrated optofluidic chip capable of analyzing cellular deformability on the basis of the pressure gradient needed to push a cell through a narrow constriction. We demonstrate the ability of the chip to discriminate between tumorigenic and metastatic breast cancer cells (MCF7 and MDA-MB231) and between human melanoma cells with different metastatic potential (A375P and A375MC2). Moreover, we show that this chip allows highlighting the effect of drugs interfering with microtubule organization (paclitaxel, combretastatin A-4 and nocodazole) on cancer cells, which leads to changes in the pressure-gradient required to push cells through the constriction. Our single-cell microfluidic device for mechanical evaluation is compact and easy to use, allowing for an extensive use in different laboratory environments.

A comprehensive strategy for the analysis of acoustic compressibility and optical deformability on single cells

“…At the state of the art, many different methods and techniques were proposed to measure cellular mechanical properties either quantitatively or qualitatively. To give a few examples, in the atomic force microscopy technique the cantilever tip is attached to the cells’ surface and the relative indentation depth at constant force is used to determine the cellular Young’s modulus 13 14 or to study cell plasma membrane tension 15 ; micropipette aspiration applies a negative pressure in the micropipette to form a gentle suction on the cell and study the local membrane deformation at the contact area 16 17 ; optical tweezers or magnetic tweezers with microbeads attached to the cell membrane can apply a very large force to the cell surface and allow for the measurement of cellular viscoelastic moduli 18 19 ; microfluidic constriction channels for cell migratory capability analysis allow studying both active and passive cell mechanical properties 20 21 22 23 . However, most of these methods require a direct cell-device contact, which could damage the studied cells during the measurement, or some of them only probe a small part of the whole cell, providing a partial data recovery and analysis.…”

Circulating tumor cell technologies

“…Deformability has been utilized as a distinguishing marker for isolating tumor cells in microfluidic platforms (Hur et al, 2011). Several studies have indicated that tumor cells exhibit greater deformability than nonmalignant cells (Cross et al, 2007;Gossett et al, 2012;Remmerbach et al, 2009), and that deformability may correspond with metastatic potential (Vazquez et al, 2015;Zhang et al, 2012). Measurements of the nuclear to cytoplasmic ratio (N/C), which may allow one to infer relative deformability, indicate that CTCs are less deformable than leukocytes; Meng et al reported average N/ C ratios of 0.8 and 0.55 for CTCs and leukocytes, respectively.…”

Biophysical isolation and identification of circulating tumor cells

“…44 ) and nuclear (heterochromatin, euchromatin, lamins, etc.) composition, 45 response to treatment, 40,46 cancer type, 42,44 the fluid microenvironment, 47 and the particular quantification technique employed, the differences between CTCs may still be small in comparison to blood cells. Work by Bagnall et al 23 suggested that 8 observed large primary CTCs behaved biophysically similar to blood cells, but they were limited by the operational cell size range their device could accommodate and could not make definitive biophysical comparisons.…”