The impact of the Hedgehog signal pathway on the tumor immune microenvironment of gastric adenocarcinoma by integrated analysis of scRNA-seq and RNA-seq datasets.

ABSTRACT

The Hedgehog signaling is a highly conserved pathway to regulate cell growth and proliferation, and plays an essential role in stomach adenocarcinoma (STAD) and other cancer types. However, previous studies were primarily conducted in terms of mRNA or vitro cell culture. It would be more convincing to integrate single-cell RNA sequencing (scRNA-seq) data because it is a more precise approach for genomic research. The expression profile, genetic alteration, and activity of the Hedgehog signaling pathway were investigated in both scRNA-seq and RNA-seq datasets of STAD. Communications between cancer cells and fibroblasts were determined by the cell-chat algorithm, and the Hedgehog-related gene signature was constructed to predict the survival of STAD. Patients were categorized into high- and low-risk groups according to the median of the signature. Further analysis explored the difference in survival outcome, tumor immune microenvironment (TIME), and drug sensitivity between the two groups, aiming to guide the use of chemotherapy and immunotherapy in STAD patients. Hedgehog signal pathway was over-activated in STAD. GAS1, GLI1, and SCEBU2 were recognized as hub genes in the prognostic signature of STAD, and served as robust risk factors to induce a poor survival outcome. Patients in the high-risk group demonstrated an exhausted TIME pattern, with rather low sensitivity toward molecular-targeted drugs. This study depicted the influence of the Hedgehog pathway on the survival outcome, TIME, and drug sensitivity of STAD, and provides novel insights for the treatment of STAD.