Silencing the Signal: The Metastasis Suppressor NDRG1 Disrupts Small Extracellular Vesicle‐Mediated Crosstalk in Pancreatic Cancer

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 overexpression of metastasis suppressor N-myc downstream regulated gene 1 (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-β), leading to attenuated ERK1/2 and p38 activation in pancreatic stellate cells (PSCs), and reduced expression of key fibrotic markers (α-SMA, FAP, and collagen 1A). NDRG1 overexpression also reduced sEVs uptake by PaC cells and diverted these to the lysosome for degradation. These findings uncover a previously unrecognized mechanism by which NDRG1 overexpression disrupts the oncogenic two-way communication between PaC cells and the TME, positioning NDRG1 overexpression as a compelling therapeutic approach against this formidable malignancy.