Role of EMT in the DNA damage response, double‐strand break repair pathway choice and its implications in cancer treatment

Abstract

Numerous epithelial–mesenchymal transition (EMT) characteristics have now been demonstrated to participate in tumor development. Indeed, EMT is involved in invasion, acquisition of stem cell properties, and therapy‐associated resistance of cancer cells. Together, these mechanisms offer advantages in adapting to changes in the tumor microenvironment. However, recent findings have shown that EMT‐associated transcription factors (EMT‐TFs) may also be involved in DNA repair. A better understanding of the coordination between the DNA repair pathways and the role played by some EMT‐TFs in the DNA damage response (DDR) should pave the way for new treatments targeting tumor‐specific molecular vulnerabilities, which result in selective destruction of cancer cells. Here we review recent advances, providing novel insights into the role of EMT in the DDR and repair pathways, with a particular focus on the influence of EMT on cellular sensitivity to damage, as well as the implications of these relationships for improving the efficacy of cancer treatments.

Suppression of Metastatic Ovarian Cancer Cells by Bepridil, a Calcium Channel Blocker

“…Transcription factors, such as Snail and β-catenin, play pivotal roles in driving the invasiveness and stemness of cancer cells during the progression of EMT [32]. For instance, Snail-and β-catenin-mediated EMT has been shown to enhance DNA-repair capacity through the activation of poly ADP-ribose polymerase (PARP) [33], as well as to induce chemoresistance by inhibiting p53-mediated apoptosis [34]. In addition, mounting evidence suggests that EMT contributes to the development of resistance to platinum-based chemotherapy in ovarian cancer [3,35,36].…”

Interplay between Partial EMT and Cisplatin Resistance as the Drivers for Recurrence in HNSCC

“…Interestingly, plasticity in HNSCC and the pEMT phenotype [ 7 , 8 , 16 ] has been consistently linked to therapy failure, especially to Cisplatin resistance [ 1 , 8 , 31 , 35 ]. pEMT cells have the potential to repair DNA damage [ 36 ], which enables tumor cells to survive Cisplatin treatments. After clinical levels of Cisplatin treatment in vitro (10 µM in vitro Cisplatin treatment corresponds to 100 mg/m 2 Cisplatin treatment in patients [ 22 ]), the following phases were observed in resistant HNSCC cells: (1) reduction of tumor cell growth, (2) giant cells survive Cisplatin treatment but do not proliferate, (3) addition of stimulatory factors enhance the regrowth of resistant epithelial cancer cell nests from the surviving giant cells [ 17 , 37 ].…”

Iron metabolism: backfire of cancer cell stemness and therapeutic modalities

“…Mani et al discovered that ectopic Twist or Snail expression, or exposure to TGF-β1, activated EMT, driving epithelial carcinoma cells into a mesenchymal state and endowing them with CSCs-like properties such as increased expression of stemness markers, in vitro sphere formation ability, and broad metastasis in vivo [ 119 , 120 ]. Simultaneously, EMT programs might regulate cancer cell self-renewal by controlling cell division modes, protect genome integrity, and facilitate DNA repair, which could explain why certain cancer cells with stem cell-like properties display high genomic stability [ 121 , 122 ]. Additionally, EMT could either modulate microenvironmental niche interactions or activate the antioxidant response, both of which are involved in CSCs stemness maintenance [ 123 – 125 ].…”