Deeper Insight in Metastatic Cancer Progression; Epithelial-to- Mesenchymal Transition and Genomic Instability: Implications on Treatment Resistance

Abstract

: Therapy resistance remains the major obstacle to successful cancer treatment. Epithelial-to- mesenchymal transition [EMT], a cellular reprogramming process involved in embryogenesis and organ development and regulated by a number of transcriptional factors [EMT-TFs] such as ZEB1/2, is recognized for its role in tumor progression and metastasis. Recently, a growing body of evidence has implicated EMT in cancer therapy resistance but the actual mechanism that underlie this finding has remained elusive. For example, whether it is, the EMT states in itself or the EMT-TFs that modulates chemo or radio-resistance in cancer is still contentious. Here, we summarise the molecular mechanisms of EMT program and chemotherapeutic resistance in cancer with specific reference to DNA damage response [DDR]. We provide an insight into the molecular interplay that exist between EMT program and DNA repair machinery in cancer and how this interaction influences therapeutic response. We review conflicting studies linking EMT and drug resistance via the DNA damage repair axis. We draw scientific evidence demonstrating how several molecular signalling, including EMT-TFs work in operational harmony to induce EMT and confer stemness properties on the EMT-susceptible cells. We highlight the role of enhanced DNA damage repair system associated with EMT-derived stem cell-like states in promoting therapy resistance and suggest a multi-targeting modality in combating cancer treatment resistance.

Dynamic EMT: a multi‐tool for tumor progression

“…Genomic instability is a common feature in cancer with evidence of contribution of EMT (Nieto et al , 2016 ; Yang et al , 2020 ) and has frequently been observed in pre‐malignant mesenchymal cells in vitro as well as in tumors (Massague, 2012 ; Comaills et al , 2016 ; Caramel et al , 2018 ; Wang et al , 2019a ). Although EMT stimuli are normally anti‐proliferative, some cancer cells maintain cell doubling, perhaps at the expense of genome stability (Omabe et al , 2021 ). The involved mechanisms overriding the anti‐proliferative signals and the generation of genomic aberrations are poorly understood.…”

“…The involved mechanisms overriding the anti‐proliferative signals and the generation of genomic aberrations are poorly understood. Usually, DNA repair, cell cycle checkpoints, senescence and cell death in response to endogenous (e.g., during DNA replication) and exogenous DNA damages (e.g., during chemotherapy) are orchestrated by the DDR, which is a conserved, multifactorial and context‐dependent signaling network (Halazonetis et al , 2008 ; Omabe et al , 2021 ). Recent evidence suggests that EMT‐TFs differentially affect the DDR.…”

Mutation Analysis of Radioresistant Early-Stage Cervical Cancer

“…In our in silico analyses, the KRAS mt / SMAD4 mt signature was associated with upregulation of the EMT phenotype and inflammatory responses. Data from multiple studies suggest an association of the EMT phenotype with radioresistance, where resistance to apoptosis and enhanced DNA damage repair capacity are often described as the underlying mechanism [ 20 , 21 , 22 , 23 ]. By contrast, the influence of enhanced inflammatory responses on cancer cell radiosensitivity is inconclusive because this phenotype can either positively or negatively influence anti-tumor immunity [ 24 ], and warrants further research.…”