Colon cancer exosome-associated HSP90B1 initiates pre-metastatic niche formation in the liver by polarizing M1 macrophage into M2 phenotype
ShuJie Li, Xue Fu, Deng Ning, QiuMeng Liu, JunFang Zhao, Qi Cheng, Xiaoping Chen, Li Jiang
Abstract
Colorectal cancer (CRC) frequently metastasizes to the liver, worsening patient outcomes. The formation of a pre-metastatic niche (PMN) is essential for this process, but how the primary colon tumor orchestrates the PMN formation remains unclear. This study investigated the role of CRC-derived exosomes using CT-26 murine colon carcinoma cells. The effects of these exosomes on immune cells, specifically M1 macrophage polarization and CD8 + T cell viability, were assessed. HSP90B1 expression in CT-26-derived exosomes was analyzed to understand its contribution to PMN formation. HSP90B1 silencing experiments were conducted to evaluate its impact on immunosuppressive PMN creation and liver metastasis. Patient blood samples were also examined to correlate exosomal HSP90B1 levels with CRC progression. Exosomes from CT-26 cells were found to polarize M1 macrophages into an M2 phenotype and decrease CD8 + T cell viability, promoting liver metastasis. High expression of HSP90B1 in CT-26 cell-derived exosomes was identified as a key factor in inducing M2 macrophage polarization and creating an immunosuppressive PMN. Silencing HSP90B1 significantly inhibited the exosome-mediated formation of the immunosuppressive PMN and reduced liver metastasis. Furthermore, elevated levels of HSP90B1 in patient-derived exosomes were associated with advanced CRC and poorer prognosis. CRC-derived exosomes promote liver metastasis by forming an immunosuppressive PMN through HSP90B1. Targeting HSP90B1 in CRC exosomes may offer a new therapeutic strategy to prevent liver metastasis and improve patient outcomes. This study elucidates the role of colorectal cancer (CRC) cell-derived exosomes in promoting liver metastasis by creating an immunosuppressive pre-metastatic niche (PMN). We demonstrate that high HSP90B1 expression in these exosomes polarizes M1 macrophages into the M2 phenotype, reducing CD8 + T cell viability. Importantly, HSP90B1 expression correlates with advanced CRC and poor patient outcomes. These findings suggest that targeting HSP90B1 in CRC-derived exosomes could offer a novel therapeutic strategy to inhibit PMN formation and prevent liver metastasis, improving clinical outcomes for CRC patients.