Exosome-derived Menin from cancer-associated fibroblasts promotes gastric cancer progression by activating the HSPA6/JNK/JunD pathway and inducing EMT.

[BACKGROUND] Our previous studies found that Menin was highly expressed in gastric cancer (GC) and could promote GC progression. Tumor microenvironment (TME), including cancer-associated fibroblasts (CAFs) and their exosomes plays pivotal roles in GC. It remains unclear whether exosomes derived from CAFs influence GC by delivering Menin.

[METHODS] Primary CAFs and normal fibroblasts (NFs) were isolated from fresh GC tissues, and co-cultured with GC cells. After Men1 expression in CAFs and NFs was modulated, exosomes were extracted via ultracentrifugation and mixed with GC cells. Next, GC cell biological behaviors were assessed in vitro. A nude mouse model of lung metastasis was established, and a small animal in vivo imaging system was used to monitor the effects of exosomes on metastasis. HSPA6/JNK/JunD pathway components and EMT-related molecules were detected by Western blot.

[RESULTS] Menin was highly expressed in CAFs and in their exosomes. Co-culturing of CAFs with GC cells promoted the proliferation, invasion and migration of GC cells. After Men1 was knocked down in CAFs, exosomes derived from these CAFs inhibited the progression of GC both in vitro and in vivo. Conversely, after overexpressing Men1, exosomes from NFs promoted the progression of GC both in vitro and in vivo. The HSPA6/JNK/JunD pathway and EMT in GC cells were activated when GC cells were co-cultured with CAFs or exosomes from Menin-overexpressing NFs.

[CONCLUSION] CAFs can promote GC progression by delivering Menin-containing exosomes, which activates the HSPA6/JNK/JunD pathway and induces EMT. Targeting Menin within CAFs and GC cells and blocking the delivery of Menin by exosomes may provide novel strategies for GC treatment.