Challenges and caveats in manipulating extracellular vesicle secretion from pancreatic cancer cells.

BACKGROUND: Extracellular vesicle (EV) signaling is important in multiple malignancies, including pancreatic ductal adenocarcinoma (PDAC). In this coordinated cell‒cell signaling mechanism, genetically altered tumor cells signal to surrounding normal cells to promote tumor progression. Many efforts have been made to mechanistically interrogate this signaling axis by inhibiting EV secretion from cells. These techniques leverage our understanding of how EV biogenesis interferes with ceramide production or GTPase activity, which aids in membrane fusion with the plasma membrane. MATERIAL AND METHODS: Our group leveraged these methods in our orthotopic PDAC mouse model to investigate the importance of PDAC EV secretion. We interfered with the GTPases Rab27a and Rab35 and utilized an inhibitor of ceramide production (GW4869) to ablate EV secretion. RESULTS AND CONCLUSION: Overall, we found that these models did not perform as anticipated, and we could not consistently inhibit KPC cell EV secretion. These results emphasize the challenges of interfering with EV secretion, as several parallel pathways, such as direct membrane budding, can compensate. Further studies are needed to develop models for studying the role of EVs in vivo.