The tumor–stroma interaction contributes to the aggressive and resistance nature of pancreatic ductal adenocarcinoma(PDAC),leading to treatment failure.Cancer-associated fibroblasts(CAFs),a key cell type in the strom...The tumor–stroma interaction contributes to the aggressive and resistance nature of pancreatic ductal adenocarcinoma(PDAC),leading to treatment failure.Cancer-associated fibroblasts(CAFs),a key cell type in the stroma,produce abundant extracellular matrix(ECM)and exhibit crosstalk with cancer cells inducing chemoresistance.In this study,we designed a cyclic peptide(cyAV3.3)targeting integrinα5(ITGA5)to disrupt CAF-induced desmoplasia and crosstalk with cancer cells.In vitro,cyAV3.3 inhibited the differentiation of pancreatic stellate cells into CAFs and reduced ECM production.In 3D co-cultured human spheroid models,the peptide decreased markers of resistance(ABCG1,BCL2,CXCR4),stemness(WNT1,CD44)and ECM remodeling(COL1A1,MMP2/9,LOX)and enhanced gemcitabine efficacy.In vivo,radiolabeled cyAV3.3 exhibited high tumor accumulation and retention following parenteral injections in a co-injection xenograft tumor model.Intriguingly,combination of cyAV3.3 with gemcitabine resulted in improved therapeutic efficacy of gemcitabine in co-injection xenograft and genetically engineered LSL-KrasG12D/+LSL-Trp53R172H/+Pdx1-Cre(KPC)PDAC models.These effects were attributed to reduced desmoplasia,vasculature compression and enhanced infiltration of cytotoxic T cells and apoptosis.This study presents a novel cyclic peptide inhibiting ITGA5-mediated tumor–stroma interaction and thereby reduce desmoplasia and resistance,ultimately enhancing chemotherapy efficacy in PDAC.展开更多
基金funded by Indonesia Endowment Fund for Education(Lembaga Pengelola Dana Pendidikan,to Deby Fajar Mardhian)ScarTec Therapeutics BV(Enschede,The Netherlands)+3 种基金Swedish Research Council(2011-5389 to Jai Prakash,The Netherlands)Dutch Organisation for Scientific Research(NWO-STW)Phase-2 grant(2017/STW/00364810 to Jai Prakash,The Netherlands)Egyptian Ministry of Higher Education and Scientific Research(20002907)Saadia A.Karim and Jennifer P.Morton were funded by a CRUK core program award to Jennifer P.Morton(A29996,UK).
文摘The tumor–stroma interaction contributes to the aggressive and resistance nature of pancreatic ductal adenocarcinoma(PDAC),leading to treatment failure.Cancer-associated fibroblasts(CAFs),a key cell type in the stroma,produce abundant extracellular matrix(ECM)and exhibit crosstalk with cancer cells inducing chemoresistance.In this study,we designed a cyclic peptide(cyAV3.3)targeting integrinα5(ITGA5)to disrupt CAF-induced desmoplasia and crosstalk with cancer cells.In vitro,cyAV3.3 inhibited the differentiation of pancreatic stellate cells into CAFs and reduced ECM production.In 3D co-cultured human spheroid models,the peptide decreased markers of resistance(ABCG1,BCL2,CXCR4),stemness(WNT1,CD44)and ECM remodeling(COL1A1,MMP2/9,LOX)and enhanced gemcitabine efficacy.In vivo,radiolabeled cyAV3.3 exhibited high tumor accumulation and retention following parenteral injections in a co-injection xenograft tumor model.Intriguingly,combination of cyAV3.3 with gemcitabine resulted in improved therapeutic efficacy of gemcitabine in co-injection xenograft and genetically engineered LSL-KrasG12D/+LSL-Trp53R172H/+Pdx1-Cre(KPC)PDAC models.These effects were attributed to reduced desmoplasia,vasculature compression and enhanced infiltration of cytotoxic T cells and apoptosis.This study presents a novel cyclic peptide inhibiting ITGA5-mediated tumor–stroma interaction and thereby reduce desmoplasia and resistance,ultimately enhancing chemotherapy efficacy in PDAC.
