Disrupting Tymp-Mediated Pathways to Block Lymph Node Metastasis in Ovarian Cancer

Historically, ovarian cancer (OC) was thought to metastasize by surface-to-surface spread, but recent developments have yielded a new understanding of the paths of metastatic spread. In epithelial ovarian cancer, the mechanisms driving lymph node (LN) metastasis are poorly understood, and it remains unclear whether omental metastasis occurs in parallel with LN metastasis. Utilizing comparative transcriptomic and proteomic profiling of primary tumors, LN metastases, and omental metastases, we identified significant upregulation of thymidine phosphorylase (TYMP) in LN metastases compared to primary and omental tumor sites. Functional studies in murine models demonstrated that TYMP silencing significantly suppressed LN metastasis, underscoring TYMP as a potential therapeutic target for impeding metastatic progression to LNs. Additionally, our data suggest that LN metastasis occurs concurrently with hematogenous spread rather than as a secondary event to omental dissemination. Furthermore, we identified that CCR7 (epithelial cancer cell)-CCL19 (macrophage or dendritic cells) axis plays a key role in LN metastasis, with TYMP knockdown resulting in reduced CCR7 expression. This work provides a new understanding of the modes of ovarian cancer metastasis and further points to TYMP as a promising target for disrupting LN metastasis.