Cellular Capsules to Look at Cell Mechanics

Here's a nice new microfluidic technique for studying cell mechanics by looking at the deformation of permeable elastic capsules as cells grow as spheroids within the confines of the capsules. This is thus a measure of the force exerted by the growing multicellular spheroids. The organization and behavior of the cells can be imaged and analyzed as well. The authors used their technique to look at tumor cell growth. They found that the compressive restoring force of the capsule results in formation of a solid-like core of denatured extracellular proteins and a peripheral rim of highly motile cells. The hyper-motile cells appear to have an invasive phenotype.

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• > Current Issue
• > vol. 110 no. 37
• > Kévin Alessandri,  14843–14848

Cellular capsules as a tool for multicellular spheroid production and for investigating the mechanics of tumor progression in vitro

1. Kévin Alessandri^a,^b,^c,^d,¹, 
2. Bibhu Ranjan Sarangi^a,^b,^c,¹, 
3. Vasily Valérïévitch Gurchenkov^a,^b,^c,^e,¹,
4. Bidisha Sinha^f, 
5. Tobias Reinhold Kießling^g, 
6. Luc Fetler^a,^b,^c, 
7. Felix Rico^h, 
8. Simon Scheuring^h,
9. Christophe Lamaze^a,^e, 
10. Anthony Simon^a,^e, 
11. Sara Geraldo^a,^e, 
12. Danijela Vignjević^a,^e, 
13. Hugo Doméjean^c,ⁱ,^j,
14. Leslie Rolland^c,ⁱ,^j, 
15. Anette Funfak^c,ⁱ,^j, 
16. Jérôme Bibette^c,ⁱ,^j, 
17. Nicolas Bremond^c,ⁱ,^j, and 
18. Pierre Nassoy^a,^b,^c,^k,^l,²
Author Affiliations

1. Edited by David A. Weitz, Harvard University, Cambridge, MA, and approved July 29, 2013 (received for review May 20, 2013)

Significance

Tumor growth intrinsically generates pressure onto the surrounding tissues, which conversely compress the tumor. These mechanical forces have been suggested to contribute to tumor growth regulation. We developed a microfluidic technique to produce 3D cell-based assays and to interrogate the interplay between tumor growth and mechanics in vitro. Multicellular spheroids are grown in permeable elastic capsules. Capsule deformation provides a direct measure of the exerted pressure. By simultaneously imaging the spheroid by confocal microscopy, we show that confinement induces a drastic cellular reorganization, including increased motility of peripheral cells. We propose that compressive stress has a beneficial impact on slowing down tumor evolution but may have a detrimental effect by triggering cell invasion and metastasis.

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Abstract

Deciphering the multifactorial determinants of tumor progression requires standardized high-throughput preparation of 3D in vitro cellular assays. We present a simple microfluidic method based on the encapsulation and growth of cells inside permeable, elastic, hollow microspheres. We show that this approach enables mass production of size-controlled multicellular spheroids. Due to their geometry and elasticity, these microcapsules can uniquely serve as quantitative mechanical sensors to measure the pressure exerted by the expanding spheroid. By monitoring the growth of individual encapsulated spheroids after confluence, we dissect the dynamics of pressure buildup toward a steady-state value, consistent with the concept of homeostatic pressure. In turn, these confining conditions are observed to increase the cellular density and affect the cellular organization of the spheroid. Postconfluent spheroids exhibit a necrotic core cemented by a blend of extracellular material and surrounded by a rim of proliferating hypermotile cells. By performing invasion assays in a collagen matrix, we report that peripheral cells readily escape preconfined spheroids and cell–cell cohesivity is maintained for freely growing spheroids, suggesting that mechanical cues from the surrounding microenvironment may trigger cell invasion from a growing tumor. Overall, our technology offers a unique avenue to produce in vitro cell-based assays useful for developing new anticancer therapies and to investigate the interplay between mechanics and growth in tumor evolution.

• tissue mechanics
 
• microfluidics
 
• tumor growth
 
• mechanotransduction