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<p>Pancreatic ductal adenocarcinoma (PDAC) is among the most aggressive and metastatic malignancies worldwide. Migrating cancer stem cells (miCSCs), marked by CD133⁺CXCR4⁺ expression is a key driver of PDAC progression, which currently lack effective therapeutic targets. Activated pancreatic stellate cells (PSCs) within the tumor microenvironment secrete CXCL12, the ligand for CXCR4, thereby promoting stemness, epithelial-to-mesenchymal transition (EMT), and chemoresistance in miCSCs. Despite advances in understanding PDAC biology, clinically effective strategies that target CXCR4⁺ CSC populations remain limited. In order to investigate the molecular mechanisms sustaining miCSCs, we performed protein–protein interaction network analysis, which identified the transcription factor BMI1 as a key downstream effector of the CXCL12/CXCR4 axis. Functional studies using shRNA-mediated knockdown of CXCR4 and BMI1 were conducted to assess their roles in miCSC migration, EMT, and self-renewal. We further evaluated the therapeutic potential of the endogenous CXCR4 antagonist EPI-X4 and its optimized derivative JM#21 in PDAC cell lines. We addressed the peptide stability by encapsulating JM#21 into mesoporous silica nanoparticles (MSNs) designed for improved half-life and sustained release under physiological conditions. BMI1 was confirmed as a critical mediator of CXCL12/CXCR4-driven stemness and EMT. Knockdown of CXCR4 or BMI1 significantly impaired miCSC maintenance and migration towards CXCL12. Both EPI-X4 and JM#21 potently inhibited CXCL12-mediated signaling, reduced EMT and stemness markers, and suppressed miCSC migratory potential. JM#21 displayed superior efficacy and re-sensitized previously resistant PDAC cell lines to gemcitabine and paclitaxel. Functional assays demonstrated that nanoparticle-loaded JM#21 more effectively suppressed EMT markers and self-renewal than the free peptide, highlighting the advantage of nanoparticle delivery in therapeutic applications. Given their biocompatibility and modularity, silica nanoparticles offer a promising platform for stabilizing peptide drugs. Our findings reveal that tumor–stroma crosstalk via the CXCL12/CXCR4/BMI1 axis plays a central role in sustaining miCSC-driven metastasis and therapy resistance in PDAC. Targeting this signaling pathway with nanoparticle-stabilized JM#21 represents a novel and clinically promising therapeutic strategy to disrupt PDAC progression and improve the efficacy of existing combination treatments.</p>

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A CXCR4 targeting peptide delivered by silica nanoparticles eliminates migrating cancer stem cells in pancreatic ductal adenocarcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月16日

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  • Kanishka Tiwary,
  • Anton Lahusen,
  • Syeda Inaas,
  • Bastian Beitzinger,
  • Roman Schmid,
  • Mirja Harms,
  • Stefanie Hauff,
  • Frank Arnold,
  • Karolin Walter,
  • Sonia Alcala,
  • Stephan Hahn,
  • Elisabeth Heßmann,
  • Alexander Kleger,
  • Ninel Azoitei,
  • Thomas Seufferlein,
  • Bruno Sainz Jr.,
  • Jan Münch,
  • Mika Lindén,
  • Patrick C. Hermann

摘要

Pancreatic ductal adenocarcinoma (PDAC) is among the most aggressive and metastatic malignancies worldwide. Migrating cancer stem cells (miCSCs), marked by CD133⁺CXCR4⁺ expression is a key driver of PDAC progression, which currently lack effective therapeutic targets. Activated pancreatic stellate cells (PSCs) within the tumor microenvironment secrete CXCL12, the ligand for CXCR4, thereby promoting stemness, epithelial-to-mesenchymal transition (EMT), and chemoresistance in miCSCs. Despite advances in understanding PDAC biology, clinically effective strategies that target CXCR4⁺ CSC populations remain limited. In order to investigate the molecular mechanisms sustaining miCSCs, we performed protein–protein interaction network analysis, which identified the transcription factor BMI1 as a key downstream effector of the CXCL12/CXCR4 axis. Functional studies using shRNA-mediated knockdown of CXCR4 and BMI1 were conducted to assess their roles in miCSC migration, EMT, and self-renewal. We further evaluated the therapeutic potential of the endogenous CXCR4 antagonist EPI-X4 and its optimized derivative JM#21 in PDAC cell lines. We addressed the peptide stability by encapsulating JM#21 into mesoporous silica nanoparticles (MSNs) designed for improved half-life and sustained release under physiological conditions. BMI1 was confirmed as a critical mediator of CXCL12/CXCR4-driven stemness and EMT. Knockdown of CXCR4 or BMI1 significantly impaired miCSC maintenance and migration towards CXCL12. Both EPI-X4 and JM#21 potently inhibited CXCL12-mediated signaling, reduced EMT and stemness markers, and suppressed miCSC migratory potential. JM#21 displayed superior efficacy and re-sensitized previously resistant PDAC cell lines to gemcitabine and paclitaxel. Functional assays demonstrated that nanoparticle-loaded JM#21 more effectively suppressed EMT markers and self-renewal than the free peptide, highlighting the advantage of nanoparticle delivery in therapeutic applications. Given their biocompatibility and modularity, silica nanoparticles offer a promising platform for stabilizing peptide drugs. Our findings reveal that tumor–stroma crosstalk via the CXCL12/CXCR4/BMI1 axis plays a central role in sustaining miCSC-driven metastasis and therapy resistance in PDAC. Targeting this signaling pathway with nanoparticle-stabilized JM#21 represents a novel and clinically promising therapeutic strategy to disrupt PDAC progression and improve the efficacy of existing combination treatments.