Single-Cell RNA sequencing reveals altered microenvironment and pro-tumoral effects of TLE4 within invasive somatotroph adenoma

Abstract Background: Invasive somatotroph adenoma, a dominant subtype of pituitary adenoma (PA), is considered a clinical challenge with limited treatments other than surgery. Single-cell transcriptome analysis provides the opportunity to characterize the cellular composition of the tumor microenvironment (TME) and elucidate the potential origin of PA cells and the mechanisms of tumor progression. Methods: We performed high-resolution single-cell RNA sequencing of 7,291 single cells obtained from invasive and noninvasive somatotroph adenomas. The alteration of the TME and the evolution of invasive PA cells were investigated in depth and verified in vivo and in vitro. Results: We constructed a single-cell transcriptional atlas and explored cell-cell interactions in the TME. The evolution and progression of invasive somatotroph adenoma were depicted from a single-cell perspective, and the key gene TLE4 was selected as the study focus. It was demonstrated by both in vivo and in vitro studies that upregulation of TLE4 in PA cells significantly enhanced tumor growth and invasive features. Additionally, according to analysis of human PA samples, high TLE4 expression was associated with larger tumor size and greater invasion. Conclusion: We described the alterations and intracellular interactions in the TME of PAs for the first time. Moreover, we revealed that TLE4 expression in PA cells is associated with PA invasion and may serve as a potential diagnostic marker or therapeutic target for PA.