Exosomes define a local and systemic communication network in healthy pancreas and pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a formidable foe, known for its aggressive nature and poor prognosis. To develop effective therapies against this lethal disease, it is essential to gain a deeper understanding of its underlying biology. In recent years, exosomes, tiny vesicles released by cells, have emerged as key players in cancer progression. However, their precise role in PDAC, particularly in living systems, has remained elusive. In a groundbreaking study, researchers at the Universidade do Porto utilized a genetically engineered mouse model, known as ExoBow, to map the spatiotemporal distribution of exosomes from healthy and PDAC pancreases in vivo, shedding light on their biological significance.

The study revealed fascinating insights into the intricate communication networks established by exosomes within the PDAC microenvironment. Cancer cells were found to establish preferential communication routes through exosomes with cancer-associated fibroblasts and endothelial cells, facilitating tumor growth and progression. Interestingly, this phenomenon was also observed in the healthy pancreas, albeit to a lesser extent. Inhibition of exosome secretion in both scenarios led to enhanced angiogenesis, highlighting the critical role of exosomes in vascularization and cancer progression.

In addition to intra-pancreatic communication, the study unveiled a significant increase in inter-organ communication in PDAC. Exosomes from PDAC pancreases targeted specific organs, including the kidneys, lungs, and thymus, indicating a systemic effect of cancer-derived exosomes. In contrast, exosome communication in healthy pancreases predominantly involved organs such as the thymus, bone marrow, brain, and intestines. This suggests a distinct pattern of inter-organ communication in PDAC compared to healthy conditions.

Schematic of the intra- and inter- pancreas communication
established by CD63 positive exosomes in PDAC

figure 8

The ExoBow mouse model can be crossed with specific Flp and Cre lines driven by the Pdx1-pancreas promoter which will render the conditional expression of CD63-XFP reporter proteins by pancreas cells. Crossing this model with well-stablished PDAC genetically engineered mouse models, enables the assessment of CD63 exosomes biodistribution locally and systemically in both healthy and PDAC contexts. Our work demonstrates an intra-pancreas connectome mediated by pancreas-derived exosomes mainly with CAFs (in a PDAC-specific context), followed by endothelial cells and, in lower amounts, with cells of the immune system. We were also able to demonstrate that the inter-pancreas connectome mediated by pancreas-derived exosomes varies from physiological conditions to a cancer context. Furthermore, we show that these routes of communication also vary along PDAC progression. PDAC, pancreatic ductal adenocarcinoma; CAFs, cancer-associated fibroblasts. Schemes created with BioRender.com.

The findings of this study shed light on the dynamic role of exosomes in orchestrating intra- and inter-organ communication networks in PDAC. By elucidating the spatiotemporal distribution and biological significance of exosomes, researchers gain valuable insights into the underlying mechanisms of cancer progression and metastasis. Furthermore, these findings pave the way for the development of targeted therapies aimed at disrupting exosome-mediated communication pathways in PDAC.

In conclusion, the study underscores the importance of exosomes in shaping the tumor microenvironment and driving cancer progression in PDAC. By leveraging advanced in vivo models and innovative techniques, researchers continue to unravel the complex biology of exosomes and their role in cancer pathogenesis. Moving forward, further investigations into exosome-mediated communication networks hold promise for the development of novel therapeutic strategies to combat this deadly disease.

Adem B, Bastos N, Ruivo CF, Sousa-Alves S, Dias C, Vieira PF, Batista IA, Cavadas B, Saur D, Machado JC, Cai D, Melo SA.(2024) Exosomes define a local and systemic communication network in healthy pancreas and pancreatic ductal adenocarcinoma. Nat Commun 15(1):1496. [article]

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