Pancreatic ductal adenocarcinoma (PDAC) is one of the most metastatic malignancies worldwide. We previously identified a distinct subset of cancer stem cells within the invasive front of patient tumors called migrating cancer stem cells (miCSCs), characterized by CD133+CXCR4+ expression. It determines the metastatic phenotype of pancreatic cancer. Therefore, targeting CXCR4 represent a potential therapeutic approach to combat metastasis in PDAC.
We examined the effect of endogenous human peptides EPI-X4 and other derivatives thereof as CXCR4 antagonist on patient-derived primary pancreatic cancer cells and tumor-stroma crosstalk. We established these peptides as novel therapeutic strategy for combating metastatic activity of PDAC using combination therapy approaches and testing in vivo delivery system eg. peptide fatty-acid (FA) conjugates and silica nanoparticles (SiNP).
Migration assay towards CXCR4 ligand CXCL12 showed that EPI-X4 and its derivatives (eg.JM#21) strongly inhibited migratory capacity in vitro. JM#21 was identified as the most potent EPI-X4 derivate. Western blot, gene expression and IF revealed that JM#21 increased Cadherin-1 expression by suppression of Snail1 via SHH pathway. Moreover, JM#21 suppressed CXCL12-induced self-renewal capacity of the tumor cells. Strikingly, JM#21 sensitized selected cell lines towards gemcitabine and paclitaxel. Furthermore, FA and SiNP combined JM#21 restricted miCSCs maintenance which was regulated via stellate cell secreted CXCL12. In serum conditions, both FA and SiNP combined JM#21 was stable and active, proving to be valuable in vivo delivery system.
In conclusion, our study reveals that targeting CXCR4 using human endogenous EPI-X4 derivates particularly JM#21 inhibits tumor-stroma crosstalk which is indispensable for miCSC maintenance. In mechanistic and preclinical set up, these peptides abrogate metastatic capacity of patient-derived pancreatic cancer cells by selective elimination of miCSCs. Moreover, tumor cells show increased susceptibility towards conventional treatment strategies enforcing EPI-X4 derivate as a novel combinatory therapy to treat metastatic pancreatic cancer.
The authors.
CRC 1279.
All authors have declared no conflicts of interest.