Tumor Evolution and Therapeutic Choice Seen through a Prism of Circulating Tumor Cell Genomic Instability

Abstract

Circulating tumor cells (CTCs) provide an accessible tool for investigating tumor heterogeneity and cell populations with metastatic potential. Although an in-depth molecular investigation is limited by the extremely low CTC count in circulation, significant progress has been made recently in single-cell analytical processes. Indeed, CTC monitoring through molecular and functional characterization may provide an understanding of genomic instability (GI) molecular mechanisms, which contribute to tumor evolution and emergence of resistant clones. In this review, we discuss the sources and consequences of GI seen through single-cell analysis of CTCs in different types of tumors. We present a detailed overview of chromosomal instability (CIN) in CTCs assessed by fluorescence in situ hybridization (FISH), and we reveal utility of CTC single-cell sequencing in identifying copy number alterations (CNA) oncogenic drivers. We highlight the role of CIN in CTC-driven metastatic progression and acquired resistance, and we comment on the technical obstacles and challenges encountered during single CTC analysis. We focus on the DNA damage response and depict DNA-repair-related dynamic biomarkers reported to date in CTCs and their role in predicting response to genotoxic treatment. In summary, the suggested relationship between genomic aberrations in CTCs and prognosis strongly supports the potential utility of GI monitoring in CTCs in clinical risk assessment and therapeutic choice.

Chromatin Separation Regulators Predict the Prognosis and Immune Microenvironment Estimation in Lung Adenocarcinoma

“…It is associated with poor outcomes and therapeutic resistance in various cancers (Potapova and Gorbsky, 2017;Bakhoum and Cantley, 2018;Kou et al, 2020a). Chromosomal segregation errors or the alteration of CSRs are usually the critical factors of genomic instability that drive tumor evolution (Hanahan and Weinberg, 2011;Bolhaqueiro et al, 2019;Tayoun et al, 2021). For example, aneuploidy is a direct consequence of chromosome segregation errors in mitosis (Janssen et al, 2011;Kawakami et al, 2019).…”

Bioinformatic identification of genomic instability-associated lncRNAs signatures for improving the clinical outcome of cervical cancer by a prognostic model

“…Genomic instability can not only initiate cancer, augment progression, and influence the overall prognosis of the affected patient, but also the survival of CC patients 3 , 5 , 22 , 23 . Recent studies have shown that epigenetic modifications and DNA damage from endogenous and exogenous sources could affect genomic instability 24 – 27 . An increasing number of reports have revealed that lncRNAs are implicated in the control of various cancer cellular disease progression 28 – 30 .…”

Circulating Tumor Cells in Breast Cancer Patients: A Balancing Act between Stemness, EMT Features and DNA Damage Responses

“…Primary tumor cells are genomically unstable, which exacerbates during tumor evolution towards CTCs through a fatal combination of aberrant cell cycle checkpoints and DNA damage responses causing replication stress [ 1 , 2 ]. Persistent replication stress increases the likelihood of the cleavage of stalled replication forks, and the resulting one-ended DNA double-strand breaks (DSBs) can be repaired by homologous recombination (HR) [ 3 ].…”

“…During their journey from the primary tumor to the distant metastatic site, CTCs undergo dramatic changes involving acquisition and a loss of stemness features, EMT and MET, detachment, migration and attachment, intravasation and extravasation, DNA damage responses to genotoxic stress, and genetic alterations conferring drug resistance [ 1 , 161 , 162 , 163 ]. Moreover, published evidence indicates that CTCs can induce systemic and localized inflammatory responses via functional neutrophil conversion, promoting metastatic seeding [ 164 , 165 ].…”