Cell fusion as a driver of metastasis: re-evaluating an old hypothesis in the age of cancer heterogeneity

Eduardo López-Collazo ^* Laura Hurtado-Navarro

• University Hospital La Paz Research Institute (IdiPAZ), Madrid, Spain

Numerous studies have investigated the molecular mechanisms and signalling pathways underlying cancer metastasis, as there is still no effective treatment for this terminal stage of the disease. However, the exact processes that enable primary cancer cells to acquire a metastatic phenotype remain unclear.Increasing attention has been focused on the fusion of cancer cells with myeloid cells, a phenomenon that may result in hybrid cells, so-called Tumour Hybrid Cells (THCs), with enhanced migratory, angiogenic, immune evasion, colonisation, and metastatic properties. This process has been shown to potentially drive tumour progression, drug resistance, and cancer recurrence. In this review, we explore the potential mechanisms that govern cancer cell fusion, the molecular mediators involved, the metastatic characteristics acquired by fusion-derived hybrids, and their clinical significance in human cancer. Additionally, we discuss emerging pharmacological strategies aimed at targeting fusogenic molecules as a means to prevent metastatic dissemination.Metastasis is the process by which cancer cells spread beyond the site of the primary niche to other parts of the organism, generating secondary tumours that can compromise the affected tissues' vital functions. This process implies that freed cancer cells, known as Circulating Tumour Cells (CTCs), leave their primary site, enter, circulate and survive in the bloodstream and lymphatic vessels, withstand their pressure, extravasate, and are finally able to reach and colonize secondary niches escaping the "combat" with immune cells (1,2).Woefully, this is the final stage for a large proportion of cancer patients, accounting for more than 90% of cancer-related deaths (3). Despite its high prevalence, metastasis is regarded as an extraordinarily inefficient process as it encompasses a series of complex challenges which include the removal of intravasated cancer cells by hemodynamic forces, immune clearance, metabolic stress,