Selective treatment pressure in colon cancer drives the molecular profile of resistant circulating tumor cell clones

• Published in: Molecular cancer Vol. 20; no. 1; p. 30
• Main Authors: Cayrefourcq, Laure, Thomas, Frédéric, Mazard, Thibault, Assenat, Eric, Assou, Said, Alix-Panabières, Catherine
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 08-02-2021; BioMed Central; BMC
• Subjects: 1-Phosphatidylinositol 3-kinase; 5-Fluorouracil; AKT protein; ALDOB; Biochemistry, Molecular Biology; Biomarkers; Biomarkers, Tumor; Biopsy; Cancer; Cancer therapies; CDA; Chemotherapy; Circulating tumor cells; Clonal evolution; Cloning; Colon cancer; Colonic Neoplasms; Colonic Neoplasms - genetics; Colonic Neoplasms - pathology; Colonic Neoplasms - therapy; Colorectal cancer; Computational Biology; Computational Biology - methods; Cytidine deaminase; Detoxification; Development and progression; Drug resistance; Drug Resistance, Neoplasm; Drug Resistance, Neoplasm - drug effects; Drug therapy; Energy metabolism; Enzymes; Gene expression; Gene Expression Profiling; Genes; Genomics; Human health and pathology; Humans; Hépatology and Gastroenterology; Letter to the Editor; Life Sciences; Liver; Liver Neoplasms; Liver Neoplasms - metabolism; Liver Neoplasms - secondary; Metabolism; Metastases; Metastasis; Neoplasm Metastasis; Neoplasm Staging; Neoplastic Cells, Circulating; Neoplastic Cells, Circulating - drug effects; Neoplastic Cells, Circulating - metabolism; Neoplastic Cells, Circulating - pathology; Patients; Peripheral blood; Physiological aspects; Precision medicine; Stem cells; TOR protein; Transcriptome; Tumor cells; Tumors; Xenobiotics; Clonal evolution; CDA; Colon cancer; ALDOB; Circulating tumor cells; Gene expression
• ISSN: 1476-4598; 1476-4598
• DOI: 10.1186/s12943-021-01326-6

The characterization of circulating tumor cells (CTCs) holds promises for precision medicine because these cells are an important clinical indicator of treatment efficacy. We established the first and still only nine permanent colon CTC lines from peripheral blood samples of a patient with metastatic colon cancer collected at different time points during treatment and cancer progression. The study objectives were (i) to compare the gene expression profiles of these CTC lines, and (ii) to determine the main features acquired during treatment. The number of upregulated genes was higher in the CTC lines obtained after treatment, indicating that they acquired properties to escape treatment pressure. Among these upregulated genes, some are involved in the mTOR and PI3K/AKT signaling pathways. Moreover, cytidine deaminase expression was significantly increased in the CTC lines obtained after failure of the first- and second-line 5-fluorouracile-based treatments, suggesting that these CTCs can eliminate this specific drug and resist to therapy. Several enzymes involved in xenobiotic metabolism also were upregulated after treatment, suggesting the activation of detoxification mechanisms in response to chemotherapy. Finally, the significant higher expression of aldolase B in four of the six CTC lines obtained after treatment withdrawal and cancer progression indicated that these clones originated from liver metastases. In conclusion, these CTC lines generated at different time points during treatment of metastatic colon cancer in a single patient are characterized by the deregulation of different genes that promote (i) drug resistance, (ii) xenobiotic and energy metabolism, and (iii) stem cell properties and plasticity.