miR-151a-3p-rich small extracellular vesicles derived from gastric cancer accelerate liver metastasis via initiating a hepatic stemness-enhancing niche

Liver metastasis (LM) severely affects gastric cancer (GC) patients' prognosis. Small extracellular vesicles (sEVs) play key roles in intercellular communication. Specific sEV-miRNAs from several types of cancer were found to induce a premetastatic niche in target organs before tumor cell arrive. However, whether the primary GC affects hepatic microenvironment or the role of sEV-miRNAs in GC-LM is yet unclear. We report that GC-derived sEVs are primarily absorbed by Kupffer cells (KCs). sEV-miR-151a-3p is highly expressed in GC-LM patients' plasma and presents poor prognosis. Treating mice with sEVs-enriched in miR-151a-3p promotes GC-LM, whereas has no influence on the proliferation of GC cells in situ. Mechanistically, sEV-miR-151a-3p inhibits SP3 in KCs. Simultaneously, sEV-miR-151a-3p targets YTHDF3 to decrease the transcriptional inhibitory activity of SP3 by reducing SUMO1 translation in a N6-methyladenosine-dependent manner. These factors contribute to TGF-beta 1 transactivation in KCs, subsequently activating the SMAD2/3 pathway and enhancing the stem cell-like properties of incoming GC cells. Furthermore, sEV-miR-151a-3p induces miR-151a-3p transcription in KCs to form a positive feedback loop. In summary, our results reveal a previously unidentified regulatory axis initiated by sEV-miR-151a-3p that establishes a hepatic stemness-permissive niche to support GC-LM. sEV-miR-151a-3p could be a promising diagnostic biomarker and preventive treatment candidate for GC-LM.

Automated summary

This study found that gastric cancer-derived sEVs are primarily absorbed by Kupffer cells, leading to high expression of sEV-miR-151a-3p in GC-LM patients with poor prognosis. These sEV-miR-151a-3p activate the SMAD2/3 pathway by inhibiting SP3 and targeting YTHDF3 in Kupffer cells, promoting liver metastasis of gastric cancer cells and enhancing stem cell-like properties. Additionally, sEV-miR-151a-3p induces miR-151a-3p transcription in Kupffer cells, forming a positive feedback loop to establish a hepatic stemness-permissive niche to support GC-LM.