Rymuza Julia, Zhang Qilin, Bujko Mateusz
Department of Molecular and Translational Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, 02-781, Poland.
Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, 200040, China.
Acta Neuropathol Commun. 2025 Aug 14;13(1):174. doi: 10.1186/s40478-025-02091-z.
Neuroendocrine pituitary tumors (PitNETs) are classified based on clinical manifestation and expression of pituitary cell lineage-specific transcription factors (TFs) and hormones. A subtype of tumors in patients with acromegaly was found to express PIT-1 and SF-1 TFs, two markers of distinct pituitary cell lineages. These tumors have been described as multilineage or "somatogonadotoph" tumors. The aim of our study was to clarify their identity and cell type origin using extensive transcriptomic analysis. For this purpose, we analyzed the RNA sequencing (RNAseq) data from 546 PitNETs (including 193 tumors of patient with acromegaly) and single cell RNAseq data from somatotroph and gonadotroph tumors and normal pituitary tissue. Somatrotroph PitNETs co-expressing PIT-1 and SF-1 TFs were identified in each of the analyzed RNAseq dataset. Their transcriptomic profile and pituitary TF activity closely resembled those of other somatotroph tumors, while differing substantially from gonadotroph PitNETs, though they retained NR5A1 (SF-1) activity and expressed some SF-1-regulated genes (e.g., LHB and GNHRH). Notably, SF-1 appeared to regulate a slightly different set of genes in double positive somatotroph PitNETs and gonadotroph tumors. Analysis of scRNAseq data revealed a subcluster of normal gonadotroph cells expressing POU1F1 (PIT-1), but tumor cells from PIT-1/SF-1 PitNETs did not resemble this normal gonadotroph cell subtype. Genes expression profiles of three subtypes of somatotroph tumors were distinguished through analyses of both bulk- and scRNAseq data. From transcriptomic perspective - based on gene co-regulation and pituitary TF activity - PitNETs of patients with acromegaly that co-express PIT-1 and SF-1 represent a subtype of PIT-1 lineage tumors, and the molecular data do not support classifying them as multilineage tumors.
神经内分泌垂体瘤（PitNETs）是根据临床表现以及垂体细胞谱系特异性转录因子（TFs）和激素的表达进行分类的。在肢端肥大症患者中发现了一种肿瘤亚型，其表达PIT-1和SF-1转录因子，这是两种不同垂体细胞谱系的标志物。这些肿瘤被描述为多谱系或“促生长促性腺激素细胞型”肿瘤。我们研究的目的是通过广泛的转录组分析来阐明它们的身份和细胞类型起源。为此，我们分析了来自546个PitNETs（包括193例肢端肥大症患者的肿瘤）的RNA测序（RNAseq）数据以及来自生长激素细胞和促性腺激素细胞肿瘤及正常垂体组织的单细胞RNAseq数据。在每个分析的RNAseq数据集中都鉴定出了共表达PIT-1和SF-1转录因子的生长激素细胞PitNETs。它们的转录组谱和垂体TF活性与其他生长激素细胞肿瘤非常相似，而与促性腺激素细胞PitNETs有很大不同，尽管它们保留了NR5A1（SF-1）活性并表达了一些SF-1调控的基因（如LHB和GNHRH）。值得注意的是，SF-1在双阳性生长激素细胞PitNETs和促性腺激素细胞肿瘤中似乎调控着略有不同的一组基因。对scRNAseq数据的分析揭示了一个表达POU1F1（PIT-1）的正常促性腺激素细胞亚群，但来自PIT-1/SF-1 PitNETs的肿瘤细胞与这种正常促性腺激素细胞亚型不同。通过对批量和scRNAseq数据的分析，区分了生长激素细胞肿瘤三种亚型的基因表达谱。从转录组学角度来看——基于基因共调控和垂体TF活性——共表达PIT-1和SF-1的肢端肥大症患者的PitNETs代表了PIT-1谱系肿瘤的一种亚型，分子数据不支持将它们分类为多谱系肿瘤。
