Biology and Function of Exosomes in Cancer

Abstract Trillions of exosomes, a subset of extracellular vesicles, are naturally present in the blood and tissue, and all cells secrete them into the extracellular milieu. Exosomes are on average around 100 nm in diameter and are speculated to have an endosomal origin, with a membrane lipid bilayer of similar orientation as the plasma membrane of the cells they originate from, and with capacity to enter other cells to deliver their constituents. The cargo exosomes include proteins, lipids, mRNA, non-coding RNAs (ncRNAs), microRNAs (miRNAs), and genomic DNA; and their production and content can vary depending on the cellular source. Exosomes may represent a novel mean of intercellular communication, but their biogenesis, trafficking, organ tropism, and impact on normal physiology and pathology in the in vivo setting is largely unknown. Similarly, the function of exosomes in pancreatic cancer remains understudied. Our research program is currently designed to address key unanswered scientific questions related to the basic biology of exosomes, their functional role in pathogenesis and therapeutic intervention of pancreatic cancer, a disease with dismal prognosis, and on the rise in the United States. Employing newly engineered mice, we propose to address the role of exosomes in the complex interplay between cancer cells, and the cells of the tumor microenvironment. Additionally, employing our established platform for clinical grade exosomes production, we will investigate the potential of engineered exosomes to target driver oncogenes and modulate the pancreatic cancer immune microenvironment/tumor immunity to facilitate therapeutic response. The proposed focus areas are rooted in the expertise we have developed within our research program over the last decade, and our track record provides the rationale and guidance for a higher chance of feasibility of the proposed studies, with potential for translational application.