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Cell Syst. 2017 Sep 27;5(3):237-250.e8. doi: 10.1016/j.cels.2017.07.005. Epub 2017 Aug 23.

Cell-Cycle Position of Single MYC-Driven Cancer Cells Dictates Their Susceptibility to a Chemotherapeutic Drug.

Author information

1
Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Bioquant Center, University of Heidelberg, 69120 Heidelberg, Germany.
2
Neuroblastoma Genomics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
3
Neuroblastoma Genomics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. Electronic address: f.westermann@dkfz.de.
4
Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Bioquant Center, University of Heidelberg, 69120 Heidelberg, Germany. Electronic address: t.hoefer@dkfz.de.

Abstract

While many tumors initially respond to chemotherapy, regrowth of surviving cells compromises treatment efficacy in the long term. The cell-biological basis of this regrowth is not understood. Here, we characterize the response of individual, patient-derived neuroblastoma cells driven by the prominent oncogene MYC to the first-line chemotherapy, doxorubicin. Combining live-cell imaging, cell-cycle-resolved transcriptomics, and mathematical modeling, we demonstrate that a cell's treatment response is dictated by its expression level of MYC and its cell-cycle position prior to treatment. All low-MYC cells enter therapy-induced senescence. High-MYC cells, by contrast, disable their cell-cycle checkpoints, forcing renewed proliferation despite treatment-induced DNA damage. After treatment, the viability of high-MYC cells depends on their cell-cycle position during treatment: newborn cells promptly halt in G1 phase, repair DNA damage, and form re-growing clones; all other cells show protracted DNA repair and ultimately die. These findings demonstrate that fast-proliferating tumor cells may resist cytotoxic treatment non-genetically, by arresting within a favorable window of the cell cycle.

KEYWORDS:

MYC; bistability; cancer; cell-cycle checkpoints; cell-cycle-resolved transcriptomics; live-cell imaging; mathematical modeling; therapy resistance

PMID:
28843484
DOI:
10.1016/j.cels.2017.07.005
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