Journal Article

Cancer-associated fibroblast-derived fibulin-5 promotes epithelial–mesenchymal transition in diffuse-type gastric cancer via cAMP response element-binding protein pathway, showing poor prognosis

Kong, Seong-Ho, Park, Miree, Cho, Soo-Jeong, Kim, Hang-Rae, Lee, Hye Seung, Kwak, Yoonjin, Choi, Jinju, Kim, Sang Gyun, Kim, Gwanghun, Jo, Jeong Yeon, Yang, Han-Kwang, Kang, Jun Hyuk, Park, Do-Joong, Kim, Jung Mogg, Myeong-Cherl, Kook, Ryu, Ji Kon, Lee, Hyuk-Joon

2025

Overview

Diffuse-type gastric cancer (DGC), characterized by poorly cohesive cells within fibrotic stroma, is associated with advanced disease and poor prognosis. Here, to identify distinct biomarkers for DGC compared with intestinal-type gastric cancer, we constructed a comprehensive large-scale signaling network using RNA-sequencing data from three genomic databases (The Cancer Genome Atlas, GSE62254 and GSE26253), developed a mathematical model and conducted simulation analyses. For validation, we used tissue microarray blocks of gastric cancers with immunohistochemical staining, single-cell RNA sequencing, primary cultures of cancer-associated fibroblasts (CAFs) and organoids, and a co-culture system involving CAFs and cancer cells. Signaling network analysis identified six differentially activated signaling components across the database, including BIRC5 , TTK , NEK2 , FHL1 , NR2F1 and FBLN5 . Among the differentially activated signaling components, high tumoral expression of fibulin-5 protein encoded by FBLN5 correlated with poor overall and disease-specific survival rates in patients with DGC, even after adjusting for the tumor, node, metastases (TNM) stage. Fibulin-5, derived from CAFs within DGC stroma, promoted organoid growth and epithelial–mesenchymal transition (EMT) in DGC cell lines via the cAMP response element-binding protein (CREB) pathway in a CAF co-culture system. FBLN5 knockdown in CAFs reduced the aggressive phenotype of co-cultured DGC cells, while CREB inhibitors reversed EMT. Furthermore, levels of secreted FBLN5 in patient blood samples correlated with its expression in primary tumors. In summary, fibulin-5 secreted by CAFs and interacted with DGC cells promotes EMT and is clinically associated with poor patient outcomes. These findings suggest fibulin-5 as a potential prognostic marker and therapeutic target in patients with DGC. Fibulin-5 identified as key marker in diffuse gastric cancer Gastric cancer is a major health concern worldwide, with two main types: intestinal and diffuse. Diffuse gastric cancer (DGC) is less common but more aggressive. Here researchers used advanced computer models to study the complex networks of genes and proteins in DGC. They focused on the protein fibulin-5 (FBLN5), which was found to be more active in DGC than in intestinal-type cancer. The study involved analyzing data from 1,139 patients and conducting experiments with cancer tissues and cells. They discovered that FBLN5, produced by cells called cancer-associated fibroblasts, helps cancer cells spread by promoting the epithelial–mesenchymal transition process. High levels of FBLN5 were linked to worse survival rates in patients with DGC. The authors concluded that FBLN5 could be a useful marker for predicting patient outcomes and a potential target for new treatments. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

• Publisher: Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group,생화학분자생물학회
• Subject: 13/1 / 13/89 / 14/105 / 14/28 / 38/61 / 38/91 / 59 / 631/67/1504/1829 / 64 / 692/53/2422 / 82 / 82/51 / 82/80 / 96/106 / 96/34 / Artificial intelligence / Biomarkers, Tumor - metabolism / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer-Associated Fibroblasts - metabolism / Cancer-Associated Fibroblasts - pathology / Cell culture / Cell Line, Tumor / Clinical outcomes / Cyclic AMP response element-binding protein / Cyclic AMP Response Element-Binding Protein - genetics / Cyclic AMP Response Element-Binding Protein - metabolism / Epithelial-Mesenchymal Transition - genetics / Extracellular Matrix Proteins - genetics / Extracellular Matrix Proteins - metabolism / Female / Fibroblasts / Gastric cancer / Gene Expression Regulation, Neoplastic / Humans / Intestine / Male / Mathematical models / Medical Biochemistry / Medical prognosis / Metastases / Molecular Medicine / Organoids / Patients / Phenotypes / Prognosis / Proteins / Signal Transduction / Stem Cells / Stomach Neoplasms - genetics / Stomach Neoplasms - metabolism / Stomach Neoplasms - mortality / Stomach Neoplasms - pathology / Stroma / Therapeutic targets / 생화학