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

  1. Kanishka Tiwary
  2. Anton Lahusen
  3. Syeda Inaas
  4. Bastian Beitzinger
  5. Roman Schmid
  6. Mirja Harms
  7. Stefanie Hauff
  8. Frank Arnold
  9. Karolin Walter
  10. Sonia Alcala
  11. Stephan Hahn
  12. Elisabeth Heßmann
  13. Alexander Kleger
  14. Ninel Azoitei
  15. Thomas Seufferlein
  16. Bruno Sainz
  17. Jan Münch
  18. Mika Lindén
  19. Patrick C. Hermann
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Abstract

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 BMI1’s 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.

Synopsis

The 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.

  • CXCL12 enhances (mi)CSC populations and metastatic potential through CXCR4 signaling.

  • BMI1 is identified as a pivotal downstream effector linking CXCR4 to EMT and stemness.

  • JM#21 effectively blocks CXCL12-induced migration, EMT, and stemness in vitro, demonstrating superior efficacy compared to other CXCR4 inhibitors.

  • Encapsulation of JM#21 in silica nanoparticles enhances its stability and delivery, reducing chemoresistance and miCSC populations in co-culture systems.

  • Combining JM#21 with chemotherapy significantly impairs colony formation and CSC-mediated drug resistance.

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  1. Version published to 10.1101/2025.03.03.641126v1 on bioRxiv