MAPK4 silencing in gastric cancer drives liver metastasis by positive feedback between cancer cells and macrophages

Liver metastasis is a major cause of death in gastric cancer patients, but the underlying mechanisms are poorly understood. Through a combination of in vivo screening and transcriptome profiling followed by quantitative RT-PCR and tissue array analyses, we found that mitogen-activated protein kinase 4 (MAPK4) downregulation in gastric cancer tissues from patients is significantly associated with liver metastasis and poor prognosis. The knockdown of MAPK4 in gastric cancer cells promotes liver metastasis in orthotopic mouse models. MAPK4 depletion in gastric cancer cells induces the secretion of macrophage migration inhibitory factor (MIF) to polarize tumor-associated macrophages (TAMs) in orthotopic xenograft tumors. Moreover, TAMs activate epithelial–mesenchymal transition of gastric cancer cells to suppress MAPK4 expression, which further increases MIF secretion to polarize TAMs. Taken together, our results suggest a previously undescribed positive feedback loop between cancer cells and macrophages mediated by MAPK4 silencing that facilitates gastric cancer liver metastasis. Gastric cancer: Gene shutdown helps spread to the liver Reduced activity of a key cell control gene mediates an interaction between gastric cancer cells and immune system cells called macrophages that allows the cancer to spread to the liver. Cancer cells migrating to the liver is a major cause of death for gastric cancer patients, but the mechanisms driving this process have been unclear. Researchers in China led by Tianhua Zhou and Wei Zhuo at Zhejiang University School of Medicine, Hangzhou, studied the activity of genes and their corresponding proteins in patients’ cancer cells, and analyzed gene activity in mouse models of gastric cancer. They found that the gene that generates a protein called MAPK4 is significantly reduced in the cancer cells. This allows the cells to interact with macrophages, promoting their spread to the liver.