Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 37, Pages 14843-14848Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1309482110
Keywords
tissue mechanics; microfluidics; tumor growth; mechanotransduction
Categories
Funding
- Agence Nationale de la Recherche [ANR-10-BLAN-1514]
- Fondation Pierre-Gilles de Gennes
- Institut National de la Sante et de la Recherche Medicale [PC201130]
- Institut Curie (Programme Incitatif et Cooperatif 3D)
- Institut National du Cancer within the Graduate School FdV
- Deutsche Forschungsgemeinschaft
- Agence Nationale de la Recherche (ANR) [ANR-10-BLAN-1514] Funding Source: Agence Nationale de la Recherche (ANR)
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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.
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