Novel peptide targeting CXCR4 disrupt tumor-stroma crosstalk to eliminate migrating cancer stem cells

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and metastatic malignancies worldwide. Migrating cancer stem cells (miCSCs) marked by CD133+CXCR4+ expression drives metastasis but lacks effective drug targets. Here, we show that activated pancreatic stellate cells secrete the CXCR4 ligand CXCL12 to foster stemness, epithelial-to-mesenchymal transition (EMT), and chemoresistance. Protein interaction network analyses links CXCL12/CXCR4 signaling axis and the downstream transcription factor BMI1. Knockdown experiments confirmed the BMI1s role in (mi)CSCs maintenance and survival. Novel CXCR4 inhibitors, i.e., the endogenous human peptide EPI-X4 and its derivatives (e.g., JM#21) strongly inhibited the in vitro migration of miCSCs. In particular, the most potent EPI-X4 derivate JM#21 sufficiently suppressed EMT, stemness, and self-renewal of human PDAC cell lines. In addition, JM#21 sensitized cell lines towards gemcitabine and paclitaxel. Overall, our study reveals that (mi)CSCs are enhanced and maintained via a tumor-stroma crosstalk through BMI1, ultimately promoting metastases and therapeutic resistance in PDAC. Peptide targeting of the CXCL12/CXCR4/BMI1 signaling axis via JM#21 could enhance PDAC combination therapies, offering a promising strategy against this deadly cancer. SynopsisThe study identifies a tumor-stroma interaction mediated by pancreatic stellate cells (PSCs) secreting CXCL12, which binds to CXCR4 on (mi)CSCs, fostering stemness, epithelial-to-mesenchymal transition (EMT), and chemoresistance. The CXCL12/CXCR4 axis activates the downstream BMI1 transcription factor, crucial for migration and stemness maintenance. O_FIG O_LINKSMALLFIG WIDTH=173 HEIGHT=200 SRC="FIGDIR/small/641126v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@14e117org.highwire.dtl.DTLVardef@c5db35org.highwire.dtl.DTLVardef@1ba7d2dorg.highwire.dtl.DTLVardef@702ccf_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LICXCL12 enhances (mi)CSC populations and metastatic potential through CXCR4 signaling. C_LIO_LIBMI1 is identified as a pivotal downstream effector linking CXCR4 to EMT and stemness. C_LIO_LIJM#21 effectively blocks CXCL12-induced migration, EMT, and stemness in vitro, demonstrating superior efficacy compared to other CXCR4 inhibitors. C_LIO_LIEncapsulation of JM#21 in silica nanoparticles enhances its stability and delivery, reducing chemoresistance and miCSC populations in co-culture systems. C_LIO_LICombining JM#21 with chemotherapy significantly impairs colony formation and CSC-mediated drug resistance. C_LI