Background 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.

Methods 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.

Results 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.

Conclusions 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.