Metastasis progression through the interplay between the immune system and Epithelial-Mesenchymal-Transition in circulating breast tumor cells

Abstract BackgroundCirculating tumor cells (CTCs) are the critical initiator of systemic dissemination of cancer, contributing to distant metastasis formation. The metastatic cascades rely on the fundamental roles of different types of CTCs. In which the dual immune responses and epithelial-mesenchymal-transition (EMT) are of two metastasis-driving phenomena and require more molecular assessments.MethodsIn this study, we investigated the transcriptomic modular pattern of single/cluster circulating tumor cells (CTCs). The co-expression analysis implemented, and we could detect two metastatic subnetworks indicating the immune responses and EMT in CTCs. Furthermore, a directed subnetwork identified in the KEGG database. The metastatic potential of subnetworks assessed and validated by classification methods on primary tumors. And, we could fit risk models to distant-metastasis survival of patients.ResultsOur results show the crosstalk among EMT, immune system, menstrual cycles, and stemness in CTCs. In which, fluctuation of menstrual cycles (hormone-related signals) is a new detected pathway in CTCs in breast cancer. The immune SVM model showed high metastatic potential in classifying patients metastatic/non-metastatic groups (accuracy, sensitivity, and specificity scores are 78%). The distant-metastasis free survival model could be used to stratify patients into low, medium, and high-risk groups. Finally, PTCRA, F13A1, LAT, ICAM2, and SNRPC are novel detected biomarkers in breast cancer.ConclusionIn conclusion, different types of CTCs, including cluster/single cells, are metastasis-leading elements in breast cancer. In which, individual assessment of their intrinsic biological properties may assist elucidating metastasis-related mechanisms. These findings may apply to develop superior treatments in the clinic.