Defective Replication Stress Response Is Inherently Linked to the Cancer Stem Cell Phenotype

Daniel J. McGrail, Curtis Chun Jen Lin, Hui Dai, Wei Mo, Yang Li, Clifford Stephan, Peter Davies, Zhimin Lu, Gordon Mills, Ju Seog Lee, Shiaw Yih Lin

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Extensive spontaneous DNA damage from oncogene-induced replication stress is ubiquitous in precancerous lesions. While this damage induces differentiation, senescence, or apoptosis in normal cells, defects in DNA replication stress response (RSR) allow cells to continue proliferating, ultimately leading to early tumorigenesis. Using systems-level approaches, we developed a replication stress response defect gene signature that predicted risk of cancer development from hyperplastic lesions. Intriguingly, we found that replication stress response defects rewire non-malignant cells into a cancer stem cell (CSC)-like state, and analysis of CSCs indicated that they inherently harbor replication stress response defects. High-throughput drug screening to elucidate molecules required for survival of replication stress response defective cells identified a dependence on MEK/ERK signaling. Inhibition of this signaling cascade restored oncogene-induced senescence through a p53-independent MDM2/p21 axis. Moreover, MEK/ERK inhibition also depleted CSC populations. Together, these findings provide insights into the role of replication stress response defects in CSCs and an actionable pathway for therapeutic targeting. Using isogenic model cell lines, McGrail et al. develop a gene signature predictive of defects in DNA replication stress response (RSR). This signature reveals that cancer stem cells (CSCs) harbor defects in replication stress response, and high-throughput drug screening identifies MEK/ERK inhibition as a targetable pathway to eradicate CSCs.

Original languageEnglish (US)
Pages (from-to)2095-2106
Number of pages12
JournalCell Reports
Volume23
Issue number7
DOIs
StatePublished - May 15 2018
Externally publishedYes

Keywords

  • cancer development
  • cancer stem cells
  • DNA damage
  • replication stress response

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    McGrail, D. J., Lin, C. C. J., Dai, H., Mo, W., Li, Y., Stephan, C., Davies, P., Lu, Z., Mills, G., Lee, J. S., & Lin, S. Y. (2018). Defective Replication Stress Response Is Inherently Linked to the Cancer Stem Cell Phenotype. Cell Reports, 23(7), 2095-2106. https://doi.org/10.1016/j.celrep.2018.04.068