Journal
ACS NANO
Volume 10, Issue 6, Pages 5835-5846Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsnano.6b00461
Keywords
rolled-up nanofilms/membranes; mitosis; chromosome segregation; membrane blebbing actin cortex; 3D cell culture; metastasis
Categories
Funding
- European Research Council under the European Union [311529]
- Volkswagen Foundation [86 362]
- FEBS Return-to-Europe fellowship
- Wellcome Trust [092096/Z/10/Z, 094587/Z/10/Z]
- European Research Council (ERC)
- DFG [1713]
- Alexander von Humboldt Foundation
- U.S. National Science Foundation [CMMI 1200241, CBET-1442014]
- Cancer Research U.K
- ERC
- European Community
- ICREA Funding Source: Custom
- Directorate For Engineering
- Div Of Chem, Bioeng, Env, & Transp Sys [1442014] Funding Source: National Science Foundation
- Directorate For Engineering
- Div Of Civil, Mechanical, & Manufact Inn [1200241] Funding Source: National Science Foundation
- Cancer Research UK [18796] Funding Source: researchfish
- Wellcome Trust [094587/Z/10/Z] Funding Source: Wellcome Trust
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In vivo, mammalian cells proliferate within 3D environments consisting of numerous microcavities and channels, which contain a variety of chemical and physical cues. External environments often differ between normal and pathological states, such as the unique spatial constraints that metastasizing cancer cells experience as they circulate the vasculature through arterioles and narrow capillaries, where they can divide and acquire elongated cylindrical shapes. While metastatic tumors cause most cancer deaths, factors impacting early cancer cell proliferation inside the vasculature and those that can promote the formation of secondary tumors remain largely unknown. Prior studies investigating confined mitosis have mainly used 2D cell culture systems. Here, we mimic aspects of metastasizing tumor cells dividing inside blood capillaries by investigating single-cell divisions of living human cancer cells, trapped inside 3D rolled-up, transparent nanomembranes. We assess the molecular effects of tubular confinement on key mitotic features, using optical high- and super-resolution microscopy. Our experiments show that tubular confinement affects the morphology and dynamics of the mitotic spindle, chromosome arrangements, and the organization of the cell cortex. Moreover, we reveal that membrane blebbing and/or associated processes act as a potential genome-safety mechanism, limiting the extent of genomic instability caused by mitosis in confined circumstances, especially in tubular 3D microenvironments. Collectively, our study demonstrates the potential of rolled-up nanomembranes for gaining molecular insights into key cellular events occurring in tubular 3D microenvironments in vivo.
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