Transcriptional Profiling of Growth Hormone–Secreting Pituitary Adenoma Stem‐Like Cells: Unveiling the Significant Role of CXCR4 in Tumorigenesis and Clinical Applications

ABSTRACT Growth hormone–secreting pituitary adenoma (GHPA) can cause excessive growth hormone production, which can lead to clinical symptoms such as acromegaly. Tumor stem cells (TSCs) are postulated to play a significant role in the development of GHPA. We performed RNA sequencing on human pituitary adenoma stem‐like cells (hPASCs) and matched bulk tumors to map a differentiation protein–protein interaction (PPI) network. The function of the C‐X‐C motif chemokine receptor‐4 (CXCR4) gene was tested in hPASCs and the GH3 cell line. The CXCR4‐based 68 Ga‐pentixafor tracer was assessed by the positron emission tomography and computed tomography (PET/CT) scanning of GHPA patients. A total of 685 differentially expressed genes were identified between hPASCs and differentiated tumor cells. Four clusters of genes were predicted, each carrying distinct biological functions. CXCR4 was pinpointed as a potential hub gene, which significantly affected the self‐renewal and differentiation of hPASCs, as well as the proliferation, invasion, and migration of GH3 cells. CXCR4 suppression decreased intra‐tumoral angiogenesis and epithelial‐to‐mesenchymal transition (EMT). CXCR4‐based 68 Ga‐pentixafor was a more adaptive tracer than 18 F‐FDG in diagnosing GHPA using PET/CT. This study provides a comprehensive genetic profiling of hPASCs and substantiates the critical role of CXCR4 in tumorigenesis, highlighting its potential in translational medicine.