Affiliation:
1. Department of Cell Biology Zhejiang University School of Medicine Hangzhou China
2. Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou China
3. Center for RNA Medicine, International Institutes of Medicine and the Fourth Affiliated Hospital Zhejiang University School of Medicine Yiwu China
4. Department of General Surgery, Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou China
5. Center for Medical Research and Innovation in Digestive System Tumors Ministry of Education Hangzhou China
6. Zhejiang University Cancer Center Hangzhou China
Abstract
AbstractCancer‐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 ΔLC and ΔCC 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.
Funder
National Natural Science Foundation of China
Subject
Genetics,Molecular Biology,Biochemistry,Biotechnology