Silencing the signal: The metastasis suppressor NDRG1 disrupts exosome-mediated crosstalk in pancreatic cancer

Abstract Pancreatic cancer (PaC) remains one of the deadliest cancers, with 5-year survival rates of 13%. A major driver of its aggressiveness is the tumour microenvironment (TME), which fuels tumour growth, metastasis, and therapeutic resistance through dynamic, bi-directional communication between cancer cells, fibroblasts, and immune cells. Emerging evidence highlights extracellular vesicles (EVs) as key mediators of oncogenic cross-talk within the PaC TME. This study demonstrates for the first time that the metastasis suppressor NDRG1 significantly influences the biogenesis, cargo packaging and release of EVs by cancer cells. This was mediated by a direct interaction between NDRG1 and ALIX, a key protein involved in EV biogenesis and packaging, with NDRG1 facilitating ALIX proteasomal degradation. Further, EVs released from NDRG1-overexpressing cells had significantly fewer CAF-activation proteins (i.e. TGF-B), leading to attenuated ERKl/2 and p38 activation in pancreatic stellate cells (PSCs), and reduced expression of key fibrotic markers (a-SMA, FAP, and collagen 1A). NDRG1 also reduced EV uptake by PaC cells and diverted these to the lysosome for degradation. These findings uncover a previously unrecognized mechanism by which NDRG1 disrupts the oncogenic two-way communication between PaC cells and the TME, positioning NDRG1 as a compelling therapeutic target against this formidable malignancy. Competing Interest Statement The authors have declared no competing interest.