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

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.

CENP-A overexpression drives distinct cell fates depending on p53 status

“…Importantly, as with the effect of CENP-A overexpression on global transcription, which underlying mechanism is at play remains to be deciphered. Since the initiation of EMT is associated with several of the cell stresses that result from mitotic defects, including genotoxic stress (Wu et al, 2013), replication stress (McGrail et al, 2018), and metabolic stress (Cha et al, 2015), amongst others (Chen et al, 2017;Jiang et al, 2017;Marcucci and Rumio, 2018;Shah and Beverly, 2015), they are likely important in the process. Interestingly, a recent report by Gomes et al demonstrated that the perturbation of the histone H3 variants, H3.1/2 and H3.3, promotes or represses EMT (Gomes et al, 2019).…”

Aneuploidy and deregulated DNA damage response define haploinsufficiency in breast tissues of BRCA2 mutation carriers

“…3C and fig. S3C) (24). This replication stress response deficiency (RSRD) signature is known to predict future cancer risk (24), and it contains some of the top most differentially expressed genes between BRCA2 mut/+ and control LP cells ( Fig.…”

“…Scale bars represent 20 m. (C) Heatmap of RNA-seq data from freshly-sorted cells shows differential expression of RSRD (replication stress response defect) genes(24) in BRCA2 mut/+ LP cells (n = 7 patients) compared to control (WT) LP cells (n = 9 patients). Columns correspond to individual patients.…”

Mechanisms for stalled replication fork stabilization: new targets for synthetic lethality strategies in cancer treatments

“…When the replication stress is prolonged, stalled replication forks can undergo irreversible fork breakage, which eventually results in genome instability . However, in the long history of evolution, cells have acquired a multitude of fork protection mechanisms to minimize the genotoxic effects of replication stress by stabilizing, repairing and restarting stalled forks, which represent important barriers to tumorigenesis in nontransformed cells . Paradoxically, these mechanisms also act in cancer cells, but only to compromise the cytotoxicity of replication stress‐inducing agents such as PARP inhibitors .…”

“…In fact, they are rather coordinated and interweaved. As replication perturbation often underlies genomic instability and chemotherapeutic strategies , this work may expand our knowledge of carcinogenesis and provide new strategies for cancer therapy.…”