Discrete pancreatic cancer extracellular vesicles reprogram stromal extracellular matrix dynamics to promote tumor progression and metastasis

Despite intense efforts in the last forty years, pancreatic cancer remains a devastating challenge for modern medicine, and is ‘on-track’ to become the 2nd leading cancer-related cause of death in the USA. In fact, about 80% of diagnosed patients die within the first year. One of the major challenges in pancreatic cancer treatment remains the “normal cells” in the cancerous tissue, which are modulated by cancer cells and help promote the spread of the malignancy. In this study, we suggest to focus on the communication between pancreatic cancer cells and cells of the connective tissue (fibroblasts) that are being “educated” by the cancer cells and promote the cancerous agenda by altering the production of pro-metastatic microenvironmental scaffolds known as the extracellular matrix. These cancer-associated fibroblasts take up small particles that shed from cancer cells. We hypothesize that these nano-sized particles (known as extracellular vesicles), which contain messenger molecules that are incorporated into the neighboring fibroblasts, can reprogram the “normal” cells affecting the manner these generate the pro-tumoral extracellular matrix. Importantly, most of pancreatic cancer patients carry a mutation in the p53 gene, which is the most mutated gene in all human cancers. By dwelling into the characterization of extracellular vesicles released by cancer cells with p53 mutation, we propose to unravel the molecular mechanisms through which pancreatic cancer cells ‘persuade’ their neighbors to participate in the malignant progress. We envision that the insights we will gain from this study will be cardinal to many patients with aggressive metastatic cancer. Targeting these cancer-associated fibroblasts and/or the discrete subsets of extracellular vesicles shed by cancer cells with p53 mutations can open new decision-making opportunities to oncologists.