Super‐Enhancer Formation in Scirrhous Gastric CAFs , and the Presence of a Stromal Field in Non‐Cancerous Tissues

Scirrhous gastric cancer has aggressive clinical courses and is characterized by dominating cancer-associated fibroblasts (CAFs). However, the origin of scirrhous CAFs remains unclear, and we here aimed to explore the epigenetic basis for scirrhous CAFs and their origin. Conditioned medium (CM) from scirrhous CAFs was shown to have a marked effect (2-4 folds) on the migration of gastric cancer cells compared to that from non-scirrhous CAFs. The aggressive phenotype of scirrhous CAFs was associated with activation of TGFβ1 and NF-κB, along with increased expression of their downstream genes. Scirrhous CAFs had heavily acetylated super-enhancers, and therapeutic targeting of super-enhancers by a BET bromodomain inhibitor, mivebresib and JQ-1, markedly decreased their migration-promoting activity. Notably, in scirrhous gastric cancer patients, normal fibroblasts in non-cancerous tissues also had a strong migration-promoting effect. It was suggested that fibroblasts in the non-cancerous tissue of scirrhous gastric patients have already acquired tumor-promoting capacity, forming a stromal field for scirrhous gastric cancer although its spatial extent remains to be solved.