Abstract

Functional Analyses of Circulating Tumor Cells in Cancer Patients

Catherine Alix-Panabieres, Associate Professor, University Medical Center of Montpellier

Circulating tumor cells (CTCs) in blood are promising new biomarkers potentially useful for prognostic prediction and monitoring of therapies in patients with solid tumors including colon cancer. Moreover, CTC research opens a new avenue for understanding the biology of metastasis in cancer patients. However, an in-depth investigation of CTCs is hampered by the very low number of these cells, especially in the blood of colorectal cancer patients. Thus, the establishment of cell cultures and permanent cell lines from CTCs has become the most challenging task over the past year.  We described, for the first time, the establishment of cell cultures and a permanent cell line from CTCs of one colon cancer patient (Cayrefourcq et al. Cancer Res. 2015). The cell line designated CTC-MCC-41 is in culture for more than three years and has been characterized at the genome, transcriptome, proteome and secretome levels. This thorough analysis showed that CTC-MCC-41 cells resemble characteristics of the original tumor cells in the colon cancer patient and display a stable phenotype characterized by an intermediate epithelial/mesenchymal phenotype, stem-cell like properties and an osteomimetic signature indicating a bone marrow origin. Functional studies showed that CTC-MCC-41 cells induced rapidly in vitro endothelial cell tube formation and in vivo tumors after xenografting in immunodeficient mice.  More recently, we defined the molecular portrait of these metastasis-competent CTCs (Alix-Panabières et al. Clin Chem. 2017). These results highlight that CTC-MCC-41 line display a very specific transcription program completely different than those of the primary and metastatic colon cancer cell lines. Interestingly, among the 1,624 transcripts exclusively up-regulated in CTC-MCC-41 samples, key genes related to energy metabolism, DNA repair and stemness genes were observed. Such data may supply insights for the discovery of new biomarkers to identify the most aggressive CTC sub-populations and for the development of new drugs to inhibit metastasis-initiator CTCs in colon cancer.  Moreover, the development of new immunotherapeutic strategies is of utmost importance. Antibodies against proteins that block the immune response of T-cells such as PDL1 have been approved for treatment of cancer patients after showing remarkable long-term remissions in subsets of patients. It is now important to develop predictive biomarkers to identify patients with the highest benefit from these therapies. In 2015, we could show for the first time that PD-L1 is heterogeneously expressed on CTCs from metastatic breast cancer patients (Mazel et al. Mol Oncol 2015). Further functional analysis of this interesting subset of CTCs might reveal special immunosuppressive properties.