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Isolation of Circulating Tumor Cells in an Orthotopic Mouse Model of Colorectal Cancer
Published on: July 18, 2017
Epigenomic reprogramming of therapy-resistant circulating tumor cells in colon cancer
Aida Bao-Caamano1,2,3, Nicolás Costa-Fraga1,2,3, Laure Cayrefourcq4,5
1Epigenomics Unit, Cancer Epigenomics, Translational Medical Oncology Group (ONCOMET), Health Research Institute of Santiago de Compostela (IDIS), University Clinical Hospital of Santiago (CHUS/SERGAS), Santiago de Compostela, Spain.
Abstract:
Therapy resistance is a major challenge in colorectal cancer management. Epigenetic changes, such as DNA methylation, in tumor cells are involved in the development of acquired resistance during treatment. Here, we characterized the DNA methylation landscape of colon circulating tumor cells (CTCs) during cancer progression and therapy resistance development. To this aim, we used nine permanent CTC lines that were derived from peripheral blood samples of a patient with metastatic colon cancer collected before treatment initiation (CTC-MCC-41) and during treatment and cancer progression (CTC-MCC-41.4 and CTC-MCC-41.5 [A-G]). We analyzed the DNA methylome of these nine CTC lines using EPIC arrays and also assessed the association between DNA methylation and gene expression profiles. We confirmed DNA methylation and gene expression results by pyrosequencing and RT-qPCR, respectively. The global DNA methylation profiles were different in the pre-treatment CTC line and in CTC lines derived during therapy resistance development. These resistant CTC lines were characterized by a more hypomethylated profile compared with the pre-treatment CTC line. Most of the observed DNA methylation differences were localized at CpG-poor regions and some in CpG islands, shore regions and promoters. We identified a distinctive DNA methylation signature that clearly differentiated the pre-treatment CTC line from the others. Of note, the genes involved in this signature were associated with cancer-relevant pathways, including PI3K/AKT, MAPK, Wnt signaling and metabolism. We identified several epigenetically deregulated genes associated with therapy resistance in CTCs, such as AP2M1. Our results bring new knowledge on the epigenomic landscape of therapy-resistant CTCs, providing novel mechanisms of resistance as well as potential biomarkers and therapeutic targets for advanced CRC management.
Insights
Epigenetic changes, specifically DNA methylation, in circulating tumor cells (CTCs) are key to understanding colorectal cancer therapy resistance. Resistant CTCs show a hypomethylated profile, revealing potential new biomarkers and drug targets.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Therapy resistance is a significant hurdle in managing colorectal cancer (CRC).
- Epigenetic alterations, particularly DNA methylation, play a crucial role in the development of acquired treatment resistance in tumor cells.
- Circulating tumor cells (CTCs) offer a window into tumor evolution and resistance mechanisms.
Purpose of the Study:
- To characterize the DNA methylation landscape of colon circulating tumor cells (CTCs) during colorectal cancer progression and the development of therapy resistance.
- To identify specific DNA methylation signatures associated with treatment resistance in CTCs.
- To explore the relationship between DNA methylation changes and gene expression in resistant CTCs.
Main Methods:
- Analysis of DNA methylome using EPIC arrays on nine permanent CTC lines derived from a metastatic colon cancer patient.
- Assessment of the association between DNA methylation and gene expression profiles.
- Validation of DNA methylation and gene expression findings using pyrosequencing and RT-qPCR, respectively.
Main Results:
- Distinct global DNA methylation profiles were observed between pre-treatment CTCs and CTCs developed during therapy resistance.
- CTCs exhibiting therapy resistance displayed a more hypomethylated profile compared to the pre-treatment CTC line.
- A unique DNA methylation signature differentiated pre-treatment CTCs from resistant CTCs, implicating genes in PI3K/AKT, MAPK, Wnt signaling, and metabolism pathways.
- Epigenetically deregulated genes, such as AP2M1, associated with therapy resistance in CTCs were identified.
Conclusions:
- The epigenomic landscape of therapy-resistant CTCs differs significantly from pre-treatment CTCs, characterized by hypomethylation.
- Specific DNA methylation signatures in CTCs can serve as potential biomarkers for advanced colorectal cancer.
- Understanding these epigenomic alterations provides insights into novel resistance mechanisms and potential therapeutic targets for colorectal cancer.
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