Fig. 1.

Classical EMT pathway for metastasis. The metastatic events start with the primary tumor producing exosome-mediated or alternative preconditioning of the metastatic path and niche (indicated by red/orange smoky trail). The metastatic environment is indicated by inset boxes. Altered glycolysis in primary tumor cells or other ECM remodeling triggers TGF-β activation by processing the latency-associate peptide (LAP) to regulate transcription by activation of receptor-regulated Smads-2/3 (R-Smads) through Smad anchor for receptor activation (SARA). Resultant EMT-inducing transcription factors induce a mesenchymal transition from epithelial phenotype while suppressing apoptosis through dysregulated polycomb repressor complex-2 (PRC2). Mesenchymal phenotype is associated with adherens junction (AJ) and tight junction (TJ) disassembly to promote migration (through FAK turnover, lamellipodia, and filopodia) and invasion (through invadopodia and podosomes to cross basement membranes) phenotypes to reach the circulation or through promoting local angiogenesis by VEGF. Inside the blood vessel, neutrophils are attracted by chemotaxis (blue smoky trail), which promotes neutrophil extracellular trap (NET) and necroptosis to facilitate vascular exit. This exposes the circulating tumor cells (CTCs) to a new microenvironment which may or may not promote the reversal of EMT (MET) through the promotion of the epithelial differentiation module (EDM). The extravasated cells use different adhesion cues (claws) to settle and adapt to the new metastatic niche. The reversibility of EMT may support another cycle of EMT and MET