Pancreatic cancer is one of the deadly malignancies with a significant mortality rate and there are currently few therapeutic options for it.The tumor microenvironment(TME)in pancreatic cancer,distinguished by fibrosi...Pancreatic cancer is one of the deadly malignancies with a significant mortality rate and there are currently few therapeutic options for it.The tumor microenvironment(TME)in pancreatic cancer,distinguished by fibrosis and the existence of cancer-associated fibroblasts(CAFs),exerts a pivotal influence on both tumor advancement and resistance to therapy.Recent advancements in the field of engineered extracellular vesicles(EVs)offer novel avenues for targeted therapy in pancreatic cancer.This study aimed to develop engineered EVs for the targeted reprogramming of CAFs and modulating the TME in pancreatic cancer.EVs obtained from bone marrow mesenchymal stem cells(BMSCs)were loaded with miR-138-5p and the anti-fibrotic agent pirfenidone(PFD)and subjected to surface modification with integrinα5-targeting peptides(named IEVs-PFD/138)to reprogram CAFs and suppress their pro-tumorigenic effects.Integrinα5-targeting peptide modification enhanced the CAF-targeting ability of EVs.miR-138-5p directly inhibited the formation of the FERMT2-TGFBR1 complex,inhibiting TGF-βsignaling pathway activation.In addition,miR-138-5p inhibited proline-mediated collagen synthesis by directly targeting the FERMT2-PYCR1 complex.The combination of miR-138-5p and PFD in EVs synergistically promoted CAF reprogramming and suppressed the pro-cancer effects of CAFs.Preclinical experiments using the orthotopic stroma-rich and patient-derived xenograft mouse models yielded promising results.In particular,IEVs-PFD/138 effectively reprogrammed CAFs and remodeled TME,which resulted in decreased tumor pressure,enhanced gemcitabine perfusion,tumor hypoxia amelioration,and greater sensitivity of cancer cells to chemotherapy.Thus,the strategy developed in this study can improve chemotherapy outcomes.Utilizing IEVs-PFD/138 as a targeted therapeutic agent to modulate CAFs and the TME represents a promising therapeutic approach for pancreatic cancer.展开更多
基金supported by National Major Scientific Research Instrument Development Project:62227803the Key Program of the National Natural Science Foundation of China:62331016+2 种基金National Natural Science Foundation of China:62141109the Leading-edge Technology Programme of Jiangsu Natural Science Foundation:BK20212012Key Research and Development Plan Project of Jiangsu Province:BE2022812.
文摘Pancreatic cancer is one of the deadly malignancies with a significant mortality rate and there are currently few therapeutic options for it.The tumor microenvironment(TME)in pancreatic cancer,distinguished by fibrosis and the existence of cancer-associated fibroblasts(CAFs),exerts a pivotal influence on both tumor advancement and resistance to therapy.Recent advancements in the field of engineered extracellular vesicles(EVs)offer novel avenues for targeted therapy in pancreatic cancer.This study aimed to develop engineered EVs for the targeted reprogramming of CAFs and modulating the TME in pancreatic cancer.EVs obtained from bone marrow mesenchymal stem cells(BMSCs)were loaded with miR-138-5p and the anti-fibrotic agent pirfenidone(PFD)and subjected to surface modification with integrinα5-targeting peptides(named IEVs-PFD/138)to reprogram CAFs and suppress their pro-tumorigenic effects.Integrinα5-targeting peptide modification enhanced the CAF-targeting ability of EVs.miR-138-5p directly inhibited the formation of the FERMT2-TGFBR1 complex,inhibiting TGF-βsignaling pathway activation.In addition,miR-138-5p inhibited proline-mediated collagen synthesis by directly targeting the FERMT2-PYCR1 complex.The combination of miR-138-5p and PFD in EVs synergistically promoted CAF reprogramming and suppressed the pro-cancer effects of CAFs.Preclinical experiments using the orthotopic stroma-rich and patient-derived xenograft mouse models yielded promising results.In particular,IEVs-PFD/138 effectively reprogrammed CAFs and remodeled TME,which resulted in decreased tumor pressure,enhanced gemcitabine perfusion,tumor hypoxia amelioration,and greater sensitivity of cancer cells to chemotherapy.Thus,the strategy developed in this study can improve chemotherapy outcomes.Utilizing IEVs-PFD/138 as a targeted therapeutic agent to modulate CAFs and the TME represents a promising therapeutic approach for pancreatic cancer.
