Molecular Insights into Division of Single Human Cancer Cells in On-Chip Transparent Microtubes
Gracias, David H
Carazo Salas, Rafael
Schmidt, Oliver G
American Chemical Society
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Xi, W., Schmidt, C., Sanchez, S., Gracias, D. H., Carazo Salas, R., Butler, R., Lawrence, N., et al. (2016). Molecular Insights into Division of Single Human Cancer Cells in On-Chip Transparent Microtubes. ACS Nano, 10 5835-5846. https://doi.org/10.1021/acsnano.6b00461
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.
3D cell culture, actin cortex, chromosome segregation, membrane blebbing, metastasis, mitosis, rolled-up nanofilms/membranes
The research leading to these results has received funding from the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ERC grant agreement no. 311529 (S.S.) and the Volkswagen Foundation no. 86 362 (S.S. and W.X.), a FEBS Return-to-Europe fellowship (C.K.S.), the Wellcome Trust (092096/Z/10/Z for N.L.; 094587/Z/10/Z for R.B.), and a European Research Council (ERC) Starting Researcher Grant (R.E.C.-S.; SYSGRO). O.G.S. acknowledges financial support from the DFG Research Unit 1713 “Sensorische Mikro und Nanosysteme”. D.H.G. acknowledges funding from the Alexander von Humboldt Foundation and the U.S. National Science Foundation (Grants: CMMI 1200241 and CBET-1442014). Research in the S.P.J. laboratory is funded by Cancer Research U.K., the ERC, and the European Community Seventh Framework Programme (DDResponse), with core infrastructure provided by Cancer Research U.K. and the Wellcome Trust.
Cancer Research UK (A18796)
Wellcome Trust (094587/Z/10/Z)
Wellcome Trust (092096/Z/10/Z)
Embargo Lift Date
External DOI: https://doi.org/10.1021/acsnano.6b00461
This record's URL: https://www.repository.cam.ac.uk/handle/1810/256484