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

Abstract

Background: Liver metastasis remains a major cause of death in colorectal cancer (CRC). Interactions between tumor cells and components of the tumor microenvironment (TME) are integral to the progression of cancer cell migration and metastatic dissemination. Investigating these cellular dynamics is essential for identifying actionable therapeutic targets. Methods: This study employed bioinformatics analysis, IHC, WB, and murine in vivo imaging to delineate the role of SPOCD1 in CRC. Additional in vitro co-culture systems, immunofluorescence, and RNA-seq were utilized to determine how SPOCD1 modulated epithelial-mesenchymal transition (EMT) through cancer-associated fibroblasts (CAFs). Mechanistic insight into SPOCD1-mediated transcriptional regulation of LAMA4 was obtained via dual-luciferase reporter assays, ChIP-qPCR, and Co-IP. Results: SPOCD1 was found to be markedly upregulated in CRC cells and exhibited potent pro-metastatic activity in vivo. Integration of external datasets with experimental validation revealed a strong correlation between SPOCD1 expression and CAFs infiltration in the TME. Further analyses demonstrated that SPOCD1 enhanced CXCL12 expression in CAFs via upregulation of LAMA4, enabling CXCL12 to engage CXCR4 on CRC cells and activate EMT signaling, thereby driving metastasis. This signaling axis was effectively interrupted by CXCR4 inhibitors. Mechanistically, SPOCD1 promoted LAMA4 expression through DNMT1 recruitment, facilitating DNA methylation-dependent transcriptional regulation. Conclusion: This study delineates a SPOCD1-centered interaction network between CRC cells and CAFs in colorectal cancer liver metastasis (CRLM), offering novel molecular candidates for therapeutic intervention in CRLM.