A specific protein present on the surface of extracellular vesicles (EVs) promotes the aggressiveness of pancreatic ductal adenocarcinoma (PDAC), according to a new study. The protein, called CD9, mediates the uptake of the EVs by pancreatic cancer cells, inducing changes in cellular function. The study also connected CD9 to poorer outcomes in patients.

The work was led by Richard Tomasini, PhD, a group leader at the Cancer Research Center of Marseille in France, and was published in Science Signaling in the article “CD9 mediates the uptake of extracellular vesicles from cancer-associated fibroblasts that promote pancreatic cancer cell aggressiveness.”

“PDAC has the worst prognosis of all solid cancers,” the researchers wrote in their article. “However, one must consider the specific cellular context of these tumors: Some 80% of PDAC masses consist of nontumor cells—mainly cancer-associated fibroblasts (CAFs), immune and nerve cells composing the intra-tumoral environment (TME), and stroma.”

Tomasini’s team previously found that EVs derived from CAFs that bear the ANXA6 protein supported tumor cell aggressiveness in PDAC. EVs are tiny compartments that ferry proteins and molecules between cells, making them a key part of cell-to-cell communication networks. Although EVs play essential roles in healthy cells, research also suggests that they may support tumor cells by allowing them to communicate with cancer-associated cells.

In the current study, the researchers have elucidated the mechanism by which these EVs support PDAC aggressiveness. The key is CD9—a protein on the surface of the CAFs and EVs.

The researchers first examined EVs from both ANXA6-positive and ANXA6-negative CAFs, which they isolated from patients with PDAC. The EVs and the CAFs harbored large amounts of CD9, which allowed surrounding PDAC cells to take in the EVs from the ANXA6-positive CAFs. When they blocked CD9, the EVs could not be taken up by the tumor cells.

Furthermore, they showed that the uptake of EVs by the tumor cells activated pathways that promoted aggressiveness. “[The] EVs induced mitogen-activated protein kinase (MAPK) pathway activity, cell migration, and epithelial-to-mesenchymal transition (EMT),” they wrote. “Blocking either CD9 or p38 MAPK signaling impaired [the] EV-induced cell migration and EMT in PDAC cells.”

Furthermore, an analysis of 951 clinical samples showed that higher amounts of CD9 correlated with poor outcomes in patients with PDAC. “This study reinforces the hypothesis that analyzing oncogenic CAF-derived EVs might be a promising way to assess prognosis and stratify patients with PDAC for targeted therapy,” the researchers wrote.

The findings could also lead to therapeutic approaches for more aggressive PDAC cases.

“The identification of CD9 as a partner of ANXA6 in CAF-derived EVs has an important impact not only on our understanding of EV uptake but also on the development of new tools targeting CAF/tumor cell cross-talk,” the researchers wrote. “[This] cross-talk . . . may represent a promising therapeutic tool and warrants further investigation.”

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