Transcriptomic landscape of Gallbladder cancer reveals altered pathways related to cell cycle and Aurora kinase

Gallbladder cancer (GBC) is a rare but aggressive biliary tract malignancy. This study explores the transcriptomic profile of GBC to identify differentially expressed genes (DEGs) and dysregulated pathways involved in its pathogenesis. RNA sequencing was performed on 13 GBC tumors and 6 matched controls. Functional enrichment analysis (FEA) as well as weighted gene co-expression network analysis (WGCNA) were used to identify dysregulated pathways, functionally relevant gene modules and hub genes. Key targets were validated in patient tissues and cell lines. A total of 1319 DEGs were identified (528 upregulated, 791 downregulated). Gene set enrichment analysis revealed activation of E2F targets and G2/M checkpoint, with downregulation of bile acid metabolism and estrogen response pathways. A tumor grade-correlated gene module was identified by WGCNA. FEA of the gene module highlighted pathways related to cell cycle and cell division. Co-expression analysis identified TPX2 as a central hub gene. Inhibitors of aurora kinase, TPX2 dependent enzyme, significantly reduced proliferation, migration, and invasion in GBC cells. Elevated Aurora kinases expression was also observed in GBC. This first transcriptomic analysis of GBC in South-East Asian Indians uncovers key drivers like TPX2 and Aurora kinases in disease progression. The study highlights cell cycle dysregulation and sex-linked signatures, offering insights for biomarker discovery and targeted therapies.