The schematic highlights key factors implicated in regulating metastasis across multiple cancers, including PDAC. Metastasis unfolds through a series of sequential steps — local invasion, intravasation, circulation, extravasation, and eventual outgrowth, each imposing distinct selective pressures on tumor cells. Intrinsic factors such as MYC or KRAS amplifications, epigenetic changes, and EMT states endow cells with invasive capabilities and enable remodeling of the TME. By secreting cytokines, chemokines, and extracellular vesicles, these invasive tumor cells recruit or reprogram myeloid cells, fibroblasts, and the ECM to facilitate local tissue invasion. Once in circulation, tumor cells travel individually or in clusters, influenced in part by whether they undergo “classical” versus partial EMT. Platelets and neutrophils also protect CTCs from immune attack (e.g., by NK cells), while cluster formation mitigates exposure to shear stress and metabolic changes (e.g., increased ROS). Dissemination can occur through lymphatic routes or along nerves, guided by specific stromal interactions. Upon reaching distant sites, tumor cells extravasate via leaky capillaries, aided by ongoing interactions with platelets and neutrophils. However, these new environments can be hostile. To overcome local barriers, tumor cells may precondition “premetastatic niches” through tumor-derived factors that induce immunosuppression and ECM remodeling. Dormancy can further enhance survival, allowing cells to adapt gradually. Many disseminated cells never progress, but others resume proliferation in response to external signals and by leveraging their intrinsic programs (e.g., EMT states, metabolic rewiring). Ultimately, site-specific interactions between tumor cells and the surrounding tissue microenvironment dictate outgrowth and metastatic heterogeneity. MET, mesenchymal-epithelial transition; PIGF, placental growth factor.