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

Cell Reports
Daniel J McGrailShiaw-Yih Lin

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.

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Citations

Aug 31, 2019·Journal of the Chinese Medical Association : JCMA·Kai-Feng HungShou-Yen Kao
Jul 3, 2020·Biomarker Research·Jing ZhangShiaw-Yih Lin
Nov 11, 2020·Cell Death and Differentiation·Katharine J HerbertGeoff S Higgins
Jan 12, 2021·Molecular Carcinogenesis·Naing L ShanNanjoo Suh
Mar 28, 2021·Communications Biology·Daniel JefferyGeneviève Almouzni
Apr 24, 2021·Genes & Development·Alyssa M KleinCarol Prives

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