Multi-omic features and clustering phenotypes of circulating tumor cells associated with metastasis and clinical outcomes

Metastasis is a lethal disease of cancer, spreading from primary tumors to the bloodstream as circulating tumor cells (CTCs), which disseminate to distant organs at low efficiency for secondary tumor regeneration, thereby contributing to unfavorable patient outcomes. The detection of dynamic CTC alterations can be indicative of cancer progression (residual cancer, aggressiveness, therapy resistance) or regression (therapy response), serving as biomarkers for diagnoses and prognoses. CTC heterogeneity is impacted by both intrinsic oncogenic changes and extrinsic microenvironmental factors (e.g. the immune system and circadian rhythm), altering the genomic/genetic, epigenomic/epigenetic, proteomic, post-translational, and metabolomic landscapes. In addition to homeostatic dynamics, regenerative stemness, and metabolic plasticity, a newly discovered feature of CTCs that influences metastatic outcomes is its intercellular clustering. While the dogma suggests that CTCs play solo as single cells in the circulation, CTCs can orchestrate with other CTCs or white blood cells to form homotypic or heterotypic multi-cellular clusters, with 20–100 times enhanced metastatic potential than single CTCs. CTC clusters promote cell survival and stemness through DNA hypomethylation and signaling pathways activated by clustering-driving proteins (CD44, CD81, ICAM1, Podocalyxin, etc). Heterotypic CTC clusters may protect CTCs from immune cell attacks if not being cleared by cytotoxic immune cells. This chapter mainly focused on CTC biology related to multi-omic features and metastatic outcomes. We speculate that CTCs could guide therapeutic targeting and be targeted specifically by anti-CTC therapeutics to reduce or eliminate cancer and cancer metastasis.