Rationale: Synergistic treatment strategies for two or more drugs have gradually developed as the main options in clinics for
cholangiocarcinoma (CCA) owing to the complicated crosstalk between the
tumor and stroma. However, the different synergetic mechanisms pose great challenges to the dosages and order of administration of drugs. Thus, a strategy for exploring and intervening in mutual targets derived from stromal cells and
cholangiocarcinoma cells was proposed. Methods: Genes with overexpression patterns in
tumors and displaying a significant association with overall survival were identified from
RNA-seq data of human CCA patients and CCA mouse models. Western blotting, qRT-PCR, immunofluorescence (IF), colony formation and flow cytometry assays were conducted to determine the
biological roles of the key oncogene in
cholangiocarcinoma and stromal cells respectively. Additionally, a dual-targeting drug delivery system (AA-HA-ODA) for cancer-associated fibroblasts (CAFs) and
tumor cells was constructed to verify the effectiveness of intervening the screened genes in vivo. Results:
Polo-like kinase 1 (PLK1) was verified to play vital role in the malignant proliferation of CCA by regulating the cell cycle pathway. PLK1 also decreased stromal production by regulating the CAF phenotype. In addition, a PLK1 inhibitor (
Ro3280) loaded dual-targeting drug delivery system (AA-HA-ODA) was prepared and exhibited high affinity for CAFs and
cholangiocarcinoma cells. The in vivo distribution pattern and antitumor efficacy of AA-HA-ODA/Ro also verify the effectiveness of inhibiting PLK1 in CCA in vivo. Conclusion: In summary, PLK1 is a mutual target derived from
tumor cells and stroma due to its crucial role in the proliferation of
tumor cells and stroma regulation in CAFs, which might provide enlightenment for multitarget treatment strategies and guidance for clinical
cholangiocarcinoma treatment.