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Transcriptomic Profiling of Lactotroph Pituitary Neuroendocrine Tumors via RNA Sequencing and Ingenuity Pathway Analysis

ABSTRACT: Background: Lactotroph pituitary neuroendocrine tumors (PitNETs) are common pituitary tumors, but their underlying molecular mechanisms remain unclear. This study aimed to investigate the transcriptomic landscape of lactotroph PitNETs and identify potential molecular mechanisms and therapeutic targets through RNA sequencing and ingenuity pathway analysis (IPA). Methods: Lactotroph PitNET tissues from five surgical cases without dopamine agonist treatment underwent RNA sequencing. Normal pituitary tissues from three patients served as controls. Differentially expressed genes (DEGs) were identified, and the functional pathways and gene networks were explored by IPA. Results: Transcriptome analysis revealed that lactotroph PitNETs had gene expression patterns that were distinct from normal pituitary tissues. We identified 1,172 upregulated DEGs, including nine long intergenic noncoding RNAs (lincRNAs) belonging to the top 30 DEGs. IPA of the upregulated DEGs showed that the estrogen receptor signaling, oxidative phosphorylation signaling, and EIF signaling were activated. In gene network analysis, key upstream regulators, such as EGR1, PRKACA, PITX2, CREB1, and JUND, may play critical roles in lactotroph PitNETs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE240781 | GEO | 2024/04/26

REPOSITORIES: GEO

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Project description:Pituitary neuroendocrine tumors (PitNET) are among the most common intracranial tumors. Despite a frequently benign course, aggressive behavior occurs for unexplained reasons, especially in functional PitNET. Tumor behavior is known to be under the influence of the tumor microenvironment (TME). However, the relationship between TME cells and aggressive tumor behavior has not been adequately explored in PitNET. We used single-cell RNA sequencing and other analyses to comparatively characterize the transcriptome of seven gonadotroph and three lactotroph PitNET and correlate it with clinical behavioral patterns. In our lactotroph PitNET samples, we detect a highly proliferative gene profile with significantly increased expression levels in tumors with aggressive behavioral patterns within a bulk RNA-seq cohort of 134 PitNET samples. We also report high intratumoral heterogeneity in both gonadotroph and lactotroph PitNET and detect gene expression programs belonging to epithelial, endocrine and immunological functional networks in both subtypes. Direct comparison of the lymphoid compartment of both subtypes reveals increased CD4+ T cell abundances in gonadotroph and increased CD4-/CD8- double negative T cell and natural killer T cell abundances in lactotroph PitNET. Also notable is the presence of proliferative lymphocytes, whose occurrence in the bulk RNA-seq cohort positively correlates with more aggressive tumor behavior. Increased CD8+ T cell and natural killer (NK) cell abundancies, however, correlate significantly with reduced aggressiveness indicating anti-tumoral effects. Our study expands the knowledge of the differences in cellular composition of functional and non-functional PitNET subtypes and lays the foundation for further studies on the influence of lymphoid cells on the variable aggressive behavior of PitNET. Regarding the treatment of drug-resistant lactotroph PitNET, proliferative lymphocytes, CD8+ T and NK cells could represent potentially valuable targets for the development of new cancer immunotherapies in the future.

Project description:Background Micro RNAs (miRNAs) are a class of small non-coding RNAs that are involved in post transcriptional gene expression regulation. miRNAS can be found in various bodily fluids including plasma. Recently circulating plasma miRNAs have been studied as biomarkers in various tumors including pituitary neuroendocrine tumors (PitNETs). However the identification of PitNET derived miRNAs in plasma remains a challenging task due to tumor volume, mass and miRNA dilution within blood. To our knowledge this is the first study that has used the NGS approach to characterize circulating miRNAs in plasma acquired from Bilateral petrosal sinus sampling (BIPSS) - a gold standard in diagnosis of ACTH secreting PitNETs. Results We sequenced plasma samples that were acquired from sinistral and dextral sides of sinus petrosus inferior and complementary plasma from peripheral venous blood (PVB). BIPSS samples were collected in three separate time periods: before administration of corticotropin releasing hormone (CRH), 5 minutes after stimulation and 15 minutes after stimulation with CRH. The highest amount of differentially expressed miRNAs was observed 5 minutes after CRH stimulation (20 upregulated, 14 downregulated). During the BIPSS procedure the highest amount of ACTH was released in the sinistral side during the 5th minute after the stimulation by CRH. In the plasma of sinistral side at the 5th minute we identified two miRNAs: hsa-miR-7-5p and hsa-miR-375-3p that were highly upregulated compared to other BIPSS samples and samples from PVB. Using clustering analysis we were able to distinguish plasma samples acquired from BIPSS from PVB plasma, indicating that the miRNA fraction characterized in this study has potentially PitNET borne origin. Conclusions In this study we provided the first insight into the landscape of circulating miRNAs in close proximity to the ACTH secreting PitNET. The data indicates that ACTH secreting PitNET releases two circulating miRNAs upon stimulation with CRH (hsa-mir-7-5p, hsa-mir-375-3p) alongside with ACTH implying the further studies of these miRNA as diagnostic markers.

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Transcriptomic Profiling of Lactotroph Pituitary Neuroendocrine Tumors via RNA Sequencing and Ingenuity Pathway Analysis

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