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

Publication date: 15 May 2018
Source:Cell Reports, Volume 23, Issue 7
Author(s): Daniel J. McGrail, Curtis Chun-Jen Lin, Hui Dai, Wei Mo, Yang Li, Clifford Stephan, Peter Davies, Zhimin Lu, Gordon B. Mills, Ju-Seog Lee, Shiaw-Yih Lin
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.

Graphical abstract

Teaser

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.


https://ift.tt/2KtKd86