Kupffer cells M2-like polarization increases liver metastatic burden via uptake of exosomal KRAS mutant protein from hypoxia colorectal carcinoma cells

Objective : This study aimed to investigate the metastasis-promoting effect of colorectal carcinoma cell-derived exosomes on liver metastasis, M2-like polarization of Kupffer cells, and the underlying mechanism. Methods : Mouse liver metastasis models were established to testify the involvement of CRC-derived exosomes on liver metastasis, and DIR and PKH26 fluorescent labeling strategies were used to trace the distribution of CRC-derived exosomes in vivo. GO and KEGG analyses of differentially expressed genes revealed the key cellular regulators and KRAS-induced signaling in CRC liver metastasis. The phenotype of Kupffer cells was determined using IHC and IF. In vitro model HMDMs were used to explore the polarization phenotype and therapeutic effects of AKT inhibition. Results : Exosome mutant KRAS induced AKT signaling in the process of kupffer cells (KCs) M2-like polarization, promoting CRC liver metastasis. AKT inhibitors may potentially be used as a therapeutic approach to prevent liver metastasis in CRC.