Extracellular Vesicle‐Packaged Linc‐ZNF25‐1 from Pancreatic Cancer Cell Promotes Pancreatic Stellate Cell Uptake of Asparagine to Advance Chemoresistance

Abstract Extensive fibrous stroma plays an important role in gemcitabine (GEM) resistance. However, the mechanism by which pancreatic cancer cells interact with pancreatic stellate cells (PSCs) to promote GEM resistance remains unclear. This study investigates the role of metabolic crosstalk between these two cells in inducing GEM resistance. Extracellular vesicles (EVs) of parental and GEM‐resistant pancreatic cancer cells are extracted and performed metabolic assays and long noncoding RNA (lncRNA) sequencing. Pancreatic cancer cell‐derived EVs promote PSCs activation and extracellular matrix formation, and GEM‐resistant pancreatic cancer cells produce more asparagine (Asn), favoring PSCs activation. Mechanistically, pancreatic cancer cell‐derived EVs mediate linc‐ZNF25‐1 to promote Asn uptake via the IGF2BP3/c‐Myc/SLC1A5 pathway in PSCs. In addition, mouse models elucidate the oncogenic function of linc‐ZNF25‐1 and the enhanced therapeutic effect of asparaginase (L‐ASNase) in combination with GEM in pancreatic cancer. This study demonstrates that pancreatic cancer cell‐derived EVs promote the uptake of Asn released from pancreatic cancer cells through the upregulation of SLC1A5 in PSCs, facilitating PSCs activation and pancreatic cancer resistance to GEM. L‐ASNase in combination with GEM is a potential therapeutic strategy for targeting stromal cells to enhance the efficacy of chemotherapeutic agents against pancreatic cancer.