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Mol Biol Cell. 2020 Feb 12:mbcE19090515. doi: 10.1091/mbc.E19-09-0515. [Epub ahead of print]

The effects of proliferation status and cell cycle phase on the responses of single cells to chemotherapy.

Author information

1
IRI Life Sciences, Humboldt University Berlin, Philippstrasse 13, 10115 Berlin, Germany.
2
Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
3
Department of Computational and Systems Biology, University of Pittsburgh Medical School, Pittsburgh PA, 15260, USA.
4
Institute of Pathology, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
5
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
6
Berlin Institute of Health (BIH), Anna-Louise-Karsch-Str. 2, 10178 Berlin, Germany.
7
University of Applied Sciences Berlin, 13353, Berlin, Germany.

Abstract

DNA damaging chemotherapeutics are widely used in cancer treatments, but for solid tumors often leave a residual tumor cell population. Here we investigated how cellular states might affect the response of individual cells in a clonal population to cisplatin, a DNA damaging chemotherapeutic agent. Using a live-cell reporter of cell cycle phase and long-term imaging, we monitored single cell proliferation before, at the time of, and after treatment. We found that in response to cisplatin, cells either arrested or died, and the ratio of these outcomes depended on the dose. While we found that cell cycle phase at the time of cisplatin addition was not predictive of outcome, the proliferative history of the cell was: highly proliferative cells were more likely to arrest than to die, whereas slowly proliferating cells showed a higher probability of death. Information theory analysis revealed that the dose of cisplatin had the greatest influence on the cells' decisions to arrest or die, and that the proliferation status interacted with the cisplatin dose to further guide this decision. These results show an unexpected effect of proliferation status on regulating responses to cisplatin, and suggest that slow proliferating cells within tumors may be acutely vulnerable to chemotherapy. [Media: see text] [Media: see text] [Media: see text] [Media: see text].

PMID:
32049575
DOI:
10.1091/mbc.E19-09-0515

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