Metastasis suppressor NDRG1 disrupts pancreatic cancer EV communication by degrading ALIX, reducing CAF activation.

Pancreatic cancer (PaC) is exceptionally lethal, with a dire 5-year survival rate of 13%. Its aggressive nature is largely driven by the tumor microenvironment (TME), which fosters growth, metastasis, and therapeutic resistance through complex cell-to-cell communication. Extracellular vesicles (EVs) are emerging as critical mediators of this oncogenic crosstalk within the PaC TME, facilitating communication between cancer cells, fibroblasts, and immune cells. Current therapies often fail to effectively target this dynamic TME communication.

In an in vitro model, researchers overexpressed N-myc downstream regulated gene 1 (NDRG1) in pancreatic cancer cells. They then analyzed the biogenesis, cargo packaging, and release of small extracellular vesicles (sEVs) from these cells. The study also investigated the interaction between NDRG1 and ALIX, a key protein in EV biogenesis, and assessed the impact of NDRG1-modified sEVs on pancreatic stellate cells (PSCs) through co-culture experiments. Uptake and degradation pathways of sEVs by PaC cells were also examined.

Overexpression of NDRG1 in pancreatic cancer cells significantly influenced the biogenesis, cargo packaging, and release of sEVs. This effect was mediated by a direct interaction between NDRG1 and ALIX, a crucial protein for EV biogenesis and packaging, with NDRG1 facilitating ALIX proteasomal degradation. > EVs released from NDRG1-overexpressing cells contained significantly fewer CAF-activation proteins, such as TGF-β, leading to attenuated ERK1/2 and p38 activation in pancreatic stellate cells (PSCs). This resulted in reduced expression of key fibrotic markers, including α-SMA, FAP, and collagen 1A, in PSCs. Furthermore, NDRG1 overexpression reduced sEV uptake by PaC cells themselves and diverted these sEVs to the lysosome for degradation, effectively disrupting the oncogenic two-way communication within the TME.