Periodontal pathogen-derived extracellular vesicles promote EGFR-dependent malignant traits in human pancreatic cancer cells

Abstract

Extracellular vesicles (EVs) produced by periodontopathic bacteria have been implicated in systemic diseases, yet their mechanistic impact on pancreatic cancer (PAC) cell behavior remains poorly defined. Here, we show that EVs derived from Aggregatibacter actinomycetemcomitans (Aa), but not from Porphyromonas gingivalis or Fusobacterium nucleatum, robustly induce epithelial-mesenchymal transition (EMT), migration, and invasion in human PAC cells. These effects require the Aa genotoxin cytolethal distending toxin (Cdt), which is selectively packaged into Aa-derived EVs and efficiently delivered to host cells. EV-associated Cdt induces DNA damage, triggers a senescence-like transcriptional program, increases EGF sensitivity, and activates the EGFR-ERK/Akt signaling axis independently of TGF{beta} signaling, thereby promoting malignant traits in vitro. Notably, these responses occur in human but not murine PAC cells, revealing species-specific susceptibility to bacterial genotoxins. Together, these findings reveal a previously unrecognized cross-kingdom mechanism by which periodontopathic bacterial EVs promote metastatic traits in human pancreatic cancer cells through Cdt-mediated DNA damage and EGFR-ERK/Akt signaling.