Exosome-Induced In Situ Oncogenic Transformation: A Hypothesis for Metastasis (EMMT)

This Perspective proposes a novel conceptual model of metastasis termed Exosome-Mediated Malignant Transformation (EMMT). In this model, dissemination occurs not through physical migration of tumor cells [1-3] but via circulating tumor exosomes (CTEs). These vesicles deliver oncogenic prion-like proteins, epigenetic regulators, and retrotransposons that selectively target distant recipient cells with unresolved DNA damage.CTE cargo includes mutant p53 R175H [15-17], aggregation-prone chaperones Hsp90α/Hsf1, chromatin-modifying enzymes such as EZH2, non-coding RNAs (miR-105-3p, lncRNA HOTAIR, circRNA ciRS-7), ADAM10/CD9+ tetraspanins, Rab27a/nSMase2, LINE-1 ORF2p, PKM2/LDHA, HIF1α, and MET/EGFR receptor cytoplasmic precursor (RCP)-recycling complexes [12,13,22-28,39]. This cargo suppresses DNA repair genes (BRCA1/2, FANCD2) and tumor suppressors, thereby perpetuating chromatin instability in vulnerable cells.Genomically susceptible cells evade apoptosis and express anchor receptors that facilitate selective CTE docking. This triggers epigenetic remodeling, chromatin disorganization, and secondary somatic mutations [37-41]. The process, termed Genetic Fixation, represents an indirect reverse information flow (protein/RNA → DNA). It synthesizes principles from six Nobel laureates (Schekman, Blobel, Prusiner, Warburg, Crick, Szostak). EMMT resolves paradoxes of classical metastasis theory and outlines a testable experimental framework using acellular preparations. The model is schematized in Figure 1.