Crosstalk Between Gastric Cancer and Adjacent Mucosa Reveals <scp>EDN1</scp>‐<scp>EDNRA</scp>‐Mediated Regulation of Cancer Stemness and Immunomodulation Networks

Within the complex system of gastric cancer, the tumour microenvironment mediates a complex network of cellular interactions, yet its tissue-specific intracellular communication patterns have remained poorly understood. Leveraging cutting-edge single-cell RNA sequencing, we investigated two independent research studies (GSE183904 and GSE184198), creating an unprecedented map of cellular crosstalk across gastric cancer tissues, their adjacent normal tissue and gastric mucosa (GM). Our systematic analysis revealed two distinct patterns: 7557 distinct interactions from normal tissue to tumour cells, while gastric mucosa engaged in 7320 unique interactions with malignant conditions. Within this cellular network, the endothelin pathway emerged as a key regulator, specifically increased in gastric mucosa-to-tumour interaction. The Cancer Genome Atlas data demonstrated that patients harbouring elevated EDNRA expression faced significantly poorer outcomes. EDNRA, previously underexplored in this context, showed remarkable upregulation across diverse gastric cancer cell lines. Through experimental validation, we demonstrated that EDNRA overexpression, when stimulated by endothelin-1, dramatically accelerated the proliferation of human gastric epithelial GSE-1 cells. Conversely, pharmacological inhibition of EDNRA using ABT-627 suppressed both NCI-N87 and MKN-28 gastric cancer cells proliferation. Further mechanistic investigation revealed the molecular mechanism of ABT-627: simultaneously triggering both extrinsic and intrinsic apoptotic cascades. TISIDB analysis revealed significant positive correlations between EDNRA and multiple immunostimulators, suggesting the role of EDNRA in immunomodulation networks. These findings reveal a previously unidentified connection between gastric mucosa and tumour progression, positioning EDNRA not only as a molecular target, but also as a critical mediator of tissue-specific cancer communication. In conclusion, EDNRA functions as both a regulatory factor and therapeutic target, offering a promising therapeutic avenue for gastric cancer intervention.