The phase separation of extracellular matrix protein matrilin-3 from cancer-associated fibroblasts contributes to gastric cancer invasion

Cancer-associated fibroblast (CAF) has emerged as a key contributor to the remodeling of tumor microenvironment through the expression and secretion of extracellular matrix (ECM) proteins, thereby promoting carcinogenesis. However, the precise contribution of ECM proteins from CAFs to gastric carcinogenesis remains poorly understood. In this study, we find that matrilin-3 (MATN3), an upregulated ECM protein associated with poorer prognosis in gastric cancer patients, originates from CAFs in gastric cancer tissues. Ectopic expression of MATN3 in CAFs significantly promotes the invasion of gastric cancer cells, which can be attenuated by neutralizing MATN3 with its antibody. Notably, a portion of MATN3 protein is found to form puncta in gastric cancer tissues ECM. MATN3 undergoes phase separation, which is mediated by its low complexity (LC) and coiled-coil (CC) domains. Moreover, overexpression of MATN3 deleted with either LC or CC in CAFs is unable to promote the invasion of gastric cancer cells, suggesting that LC or CC domain is required for the effect of CAF-secreted MATN3 in gastric cancer cell invasion. Additionally, orthotopic co-injection of gastric cancer cells and CAFs expressing MATN3, but not its Delta LC and Delta CC mutants, leads to enhanced gastric cancer cell invasion in mouse models. Collectively, our works suggest that MATN3 is secreted by CAFs and undergoes phase separation, which promotes gastric cancer invasion. The ECM protein matrilin-3 (MATN3) is upregulated and associated with poorer prognosis in gastric cancer patients. MATN3 mainly derives from CAFs and forms phase-separated puncta in ECM of human gastric cancer tissues. CAFs-secreted MATN3 promotes invasion of gastric cancer cells and enhances their invasive ability in the orthotopically co-injected mouse model. Together, our study suggests that CAFs-secreted MATN3 undergoes phase separation and promotes gastric cancer invasion.image