IDDF2024-ABS-0445 PLOD2 promotes colorectal cancer liver metastasis by secreting exosome to mediate macrophages senescence

<h3>Background</h3> Liver metastasis remains a major obstacle to the long-term survival of colorectal cancer patients. Senescent cells play relevant but context-dependent roles during tumorigenesis. The communication between cancer-derived exosomes and stroma plays an irreplaceable role in facilitating pre-metastatic niche formation and cancer metastasis. However, the mechanisms underlying exosome-mediated colorectal cancer liver metastasis (CRLM) remain incompletely understood. Here, we demonstrated that the exosome from PLOD2- upregulated -CRC cell facilitated CRLM through altering their local microenvironment. <h3>Methods</h3> Immunofluorescent analyses evaluated the intake of exosome. LC–MS/MS proteomic profiling identified the change between exosome from HCT116 ^PLOD-wt and HCT116 ^PLOD-KO. Single-cell RNA sequencing was conducted on CRLM in a mouse model to gain further insight into the pre-metastatic microenvironment. SA-β-gal staining assays were used to measure cellular senescence. Blood sera, CRLM tumor tissue samples, and tissue array were included for clinical correlations. <h3>Results</h3> Patients with CRLM exhibited an upregulated expression of PLOD2 in primary tumors than those without CRLM. Downregulation of PLOD2 could reduce the CRLM in a mouse model. In an exosome education CRLM mouse model, we found that senescent macrophages were accumulated in the HCT116 ^PLOD-wt mouse model. The addition of exosome from HCT116 ^PLOD-wt actively fused with macrophages and transferred a senescent phenotype. <h3>Conclusions</h3> Collectively, our data suggests PLOD2 can support colorectal cancer transforming to the liver by altering the local liver microenvironment, providing new insight into therapy for CRLM patients.