Deciphering the interactions between tumor and stromal cells is a growing field of research to improve pancreatic cancer-associated therapies and patients’ care. Indeed, while accounting for 50 to 90% of the tumor mass, many pieces of evidence reported that beyond their structural role, the non-tumoral cells composing the intra-tumoral microenvironment influence tumor cells’ proliferation, metabolism, cell death and resistance to therapies, among others. Simultaneously, tumor cells can influence non-tumoral neighboring or distant cells in order to shape a tumor-supportive and immunosuppressive environment as well as influencing the formation of metastatic niches. Among intercellular modes of communication, extracellular vesicles can simultaneously transfer the largest variety of signals and were recently reported as key effectors of cell–cell communication in pancreatic cancer, from its development to its evolution as well as its ability to resist available treatments. This review focuses on extracellular vesicles-mediated communication between different cellular components of pancreatic tumors, from the modulation of cellular activities and abilities to their biological and physiological relevance. Taking into consideration the intra-tumoral microenvironment and its extracellular-mediated crosstalk as main drivers of pancreatic cancer development should open up new therapeutic windows.
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