Cancer cell SPOCD1 promotes colorectal cancer liver metastasis by activating the CXCL12/CXCR4 signaling pathway in cancer-associated fibroblasts

Background Liver metastasis is one of the leading causes of death in colorectal cancer (CRC). The interaction between tumor cells and components of the tumor microenvironment (TME) plays an irreplaceable role in promoting cancer cell migration and metastasis. Therefore, exploring these interactions may be key to developing effective treatment strategies. Methods In this study, we utilized bioinformatics analysis, IHC, WB, and in vivo imaging in mice to elucidate the function of SPOCD1 in CRC. Furthermore, through in vitro co-culture, immunofluorescence, and RNA-seq, we revealed that SPOCD1 promotes epithelial-mesenchymal transition (EMT) in cancer cells via cancer-associated fibroblasts (CAFs). Finally, we identified the role of SPOCD1 in regulating LAMA4 transcription through dual-luciferase assays, ChIP-qPCR, and Co-IP. Results Here, we found that SPOCD1, a pro-cancer molecule, is highly expressed in CRC cells and has a significant pro-metastatic effect in vivo. Further integration of external datasets and in vivo and in vitro experiments revealed that SPOCD1 is closely associated with the infiltration of CAFs in the TME. Next, we confirmed that SPOCD1 can increase the expression of the chemokine CXCL12 in CAFs through LAMA4, which then binds to the CXCR4 receptor on CRC cells, promoting EMT and thereby mediating tumor cell metastasis. This process can be blocked by CXCR4 inhibitors. Finally, we discovered that SPOCD1 regulates LAMA4 expression by recruiting DNMT1 to exert DNA methylation functions. Conclusion In summary, we unveiled an interaction network between cancer cells and CAFs based on SPOCD1 in colorectal cancer liver metastasis (CRLM), providing potential molecular targets for the treatment of CRLM.