Relevance of circulating hybrid cells as a non-invasive biomarker for myriad solid tumors

Abstract

Metastatic progression defines the final stages of tumor evolution and underlies the majority of cancer-related deaths. The heterogeneity in disseminated tumor cell populations capable of seeding and growing in distant organ sites contributes to the development of treatment resistant disease. We recently reported the identification of a novel tumor-derived cell population, circulating hybrid cells (CHCs), harboring attributes from both macrophages and neoplastic cells, including functional characteristics important to metastatic spread. These disseminated hybrids outnumber conventionally defined circulating tumor cells (CTCs) in cancer patients. It is unknown if CHCs represent a generalized cancer mechanism for cell dissemination, or if this population is relevant to the metastatic cascade. Herein, we detect CHCs in the peripheral blood of patients with cancer in myriad disease sites encompassing epithelial and non-epithelial malignancies. Further, we demonstrate that in vivo-derived hybrid cells harbor tumor-initiating capacity in murine cancer models and that CHCs from human breast cancer patients express stem cell antigens, features consistent with the potential to seed and grow at metastatic sites. Finally, we reveal heterogeneity of CHC phenotypes reflect key tumor features, including oncogenic mutations and functional protein expression. Importantly, this novel population of disseminated neoplastic cells opens a new area in cancer biology and renewed opportunity for battling metastatic disease.

Heterogeneity of circulating epithelial cells in breast cancer at single-cell resolution: identifying tumor and hybrid cells

“…Only one population of aneuploid CD45 ─ CECs demonstrated the most transcriptional cancer features that may indicate the presence of an aggressive subset of CTCs. Interestingly, no important molecular features were identified in aneuploid CD45 + CECs; however, tumor hybrid cells are known to have increased proliferation and migration, drug resistance, decreased apoptosis rate, and avoiding immune surveillance [14][15][16] . Diploid CD45 ─ and CD45 + CECs included different normal cells (stem, bone marrowderived mononuclear, B, T, and NK cells) and were enriched by Th1 and Th2 cell differentiation, oxidative phosphorylation hematopoietic cell lineage, necroptosis, and other signaling pathways.…”

Tumor Hybrid Cells: Nature and Biological Significance

“…For instance, a comparison of hybrid clone cells formed by spontaneous fusion events of human M13SV1-EGFP-Neo breast epithelial cells and HS578T-Hyg, MDA-MB-435-Hyg, and MDA-MB-231-Hyg cancer cells demonstrated that fusion cells formed by HS578 cells had stronger in vitro tumor-initiating traits as compared to those formed by MDA-MB-231 and MDA-MB-453 cells, as identified by surface marker (frequency of ALDH1+ cells) and functional (mammosphere) assays ( Fahlbusch et al, 2020 ). Similarly, hybrid cells in circulation were shown to reflect the heterogeneity of both epithelial and non-epithelial malignancies and can be used as a translational non-invasive readout of tumor aggressiveness, given their higher frequency than that of CTCs ( Dietz et al, 2021 ). Hybrid clones can also be metabolically heterogeneous, as noted for subpopulations of CSCs with varying EMT phenotypes ( Luo et al, 2018 ), but overall, they display an enriched Warburg-like phenotype (upregulated glycolysis) ( Brito et al, 2021 ).…”

Hybrid/Atypical Forms of Circulating Tumor Cells: Current State of the Art

“…These cells were called “circulating hybrid cells” or CHCs. They were also detected in the blood of oncological patients in numbers far larger than the quantities of CTCs – on average approximately 5-70 cells per 500,000 live cells depending on the type of oncological disease, up to thousands in the cases of uveal melanoma [ 61 ]. It was hypothesized that CHCs are the products of cell fusion, when CAMLs are produced as a result of engulfing of cancer cells [ 57 ].…”