Cancer-Associated Fibroblasts Promote Lymphatic Metastasis in Cholangiocarcinoma <i>via</i> the PDGF-BB/PDGFR-β Mediated Paracrine Signaling Network
Jian Yan, Gang Xiao, Caini Yang, Qinqin Liu, Cui Lv, Xianhuan Yu, Ziyu Zhou, Shusheng Lin, Zhenhua Bai, Haoming Lin, Rui Zhang, Chao Liu
Abstract
Patients with cholangiocarcinoma (CCA) with lymph node metastasis (LNM) have the worst prognosis, even after complete resection; however, the underlying mechanism remains unclear. Here, we established CAF-derived PDGF-BB as a regulator of LMN in CCA. Proteomics analysis revealed upregulation of PDGF-BB in CAFs derived from patients with CCA with LMN (LN<sup>+</sup>CAFs). Clinically, the expression of CAF-PDGF-BB correlated with poor prognosis and increased LMN in patients with CCA, while CAF-secreted PDGF-BB enhanced lymphatic endothelial cell (LEC)-mediated lymphangiogenesis and promoted the trans-LEC migration ability of tumor cells. Co-injection of LN<sup>+</sup>CAFs and cancer cells increased tumor growth and LMN <i>in vivo</i>. Mechanistically, CAF-derived PDGF-BB activated its receptor PDGFR-β and its downstream ERK1/2-JNK signaling pathways in LECs to promote lymphoangiogenesis, while it also upregulated the PDGFR-β-GSK-P65-mediated tumor cell migration. Finally, targeting PDGF-BB/PDGFR-β or the GSK-P65 signaling axis prohibited CAF-mediated popliteal lymphatic metastasis (PLM) <i>in vivo</i>. Overall, our findings revealed that CAFs promote tumor growth and LMN via a paracrine network, identifying a promising therapeutic target for patients with advanced CCA.