title: Cellular capsules as a tool for multicellular spheroid production and for investigating the mechanics of tumor progression in vitro.
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.
authors: Institut Curie, 75005 Paris, France.
authors: Kévin
authors: K
authors: Alessandri
authors: Bibhu Ranjan
authors: BR
authors: Sarangi
authors: Vasily Valérïévitch
authors: VV
authors: Gurchenkov
authors: Bidisha
authors: B
authors: Sinha
authors: Tobias Reinhold
authors: TR
authors: Kießling
authors: Luc
authors: L
authors: Fetler
authors: Felix
authors: F
authors: Rico
authors: Simon
authors: S
authors: Scheuring
authors: Christophe
authors: C
authors: Lamaze
authors: Anthony
authors: A
authors: Simon
authors: Sara
authors: S
authors: Geraldo
authors: Danijela
authors: D
authors: Vignjevic
authors: Hugo
authors: H
authors: Doméjean
authors: Leslie
authors: L
authors: Rolland
authors: Anette
authors: A
authors: Funfak
authors: Jérôme
authors: J
authors: Bibette
authors: Nicolas
authors: N
authors: Bremond
authors: Pierre
authors: P
authors: Nassoy
mesh_terms: D000464:Alginates; D000818:Animals; D001696:Biomechanical Phenomena; D002214:Capsules; D002452:Cell Count; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D018450:Disease Progression; D004548:Elasticity; D020723:Glucuronic Acid; D006367:HeLa Cells; D006603:Hexuronic Acids; D006801:Humans; D040542:Mechanotransduction, Cellular; D051379:Mice; D046210:Microfluidic Analytical Techniques / Q000295:instrumentation; D009361:Neoplasm Invasiveness / Q000473:pathology* / Q000503:physiopathology*; D018874:Spheroids, Cellular / Q000473:pathology* / Q000502:physiology*; D059016:Tumor Microenvironment
chemical_list: D000464:Alginates; D002214:Capsules; D006603:Hexuronic Acids; D020723:Glucuronic Acid
keywords: mechanotransduction; microfluidics; tissue mechanics; tumor growth
references: Integr Biol (Camb). 2009 Dec;1(11-12):649-54
references: 20027373
references: Proc Natl Acad Sci U S A. 2008 Jan 8;105(1):59-63
references: 18160535
references: Biol Proced Online. 2009 May 15;11:32-51
references: 19495910
references: J Control Release. 1999 Mar 8;58(1):21-8
references: 10021486
references: Macromol Biosci. 2006 Aug 7;6(8):623-33
references: 16881042
references: PLoS One. 2009;4(2):e4632
references: 19247489
references: Phys Biol. 2005 Jul 12;2(3):133-47
references: 16224119
references: Lab Chip. 2011 Jan 21;11(2):246-52
references: 20967338
references: Nat Rev Cancer. 2009 Feb;9(2):108-22
references: 19165226
references: J Cell Biol. 2004 Dec 20;167(6):1183-94
references: 15596540
references: Biomed Microdevices. 2010 Aug;12(4):647-54
references: 20237849
references: Trends Cell Biol. 2011 Jan;21(1):47-56
references: 20870407
references: Science. 2001 Nov 23;294(5547):1708-12
references: 11721053
references: Biotechnol Bioeng. 1984 Jan;26(1):53-8
references: 18551586
references: Cancer Res. 1986 Jul;46(7):3504-12
references: 3708582
references: Lab Chip. 2011 Mar 21;11(6):1168-73
references: 21298129
references: Nat Biotechnol. 1997 Aug;15(8):778-83
references: 9255794
references: HFSP J. 2009 Aug;3(4):265-72
references: 20119483
references: Breast Cancer Res Treat. 2004 Jun;85(3):281-91
references: 15111767
references: Phys Rev E Stat Nonlin Soft Matter Phys. 2009 May;79(5 Pt 1):051907
references: 19518480
references: Hum Reprod. 2012 Jun;27(6):1801-10
references: 22456922
references: Science. 1988 Apr 8;240(4849):177-84
references: 2451290
references: Nat Methods. 2007 Apr;4(4):359-65
references: 17396127
references: Proc Natl Acad Sci U S A. 2012 Jan 17;109(3):911-6
references: 22203958
references: J Biotechnol. 2010 Jul 1;148(1):3-15
references: 20097238
references: Phys Rev Lett. 2011 Oct 28;107(18):188102
references: 22107677