Single-cell sequencing identifies differentiation-related markers for molecular classification and recurrence prediction of PitNET

Zhang, Qilin; Yao, Boyuan; Long, Xin; Chen, Zhengyuan; He, Min; Wu, Yang; Qiao, Na; Ma, Zengyi; Zhao, Yupei; Zhang, Yichao; Yao, Shun; Wang, Ye; Cheng, Haixia; Chen, Hong; Ye, Hongying; Wang, Yongfei; Li, Yimin; Chen, Jianhua; Zhang, Zhaoyun; Guo, Fan; Zhao, Yao

doi:10.1016/j.xcrm.2023.100934

Cited by 17 publications

(17 citation statements)

References 85 publications

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“…Here, we further highlighted the tumor heterogeneity and TIME of three transcription factor(TF)-based lineages in PitNETs from a single-cell perspective. Our results complement previous studies concerning the heterogeneity of different lineages in PitNETs [ 3 , 5 , 6 ]. We identified that different lineages of PitNET not only have distinct characteristics in TF-related transcriptomic profiles and functional modules but also exhibit genetic variation and CNVs.…”

Section: Discussionsupporting

confidence: 91%

“…Among these, the POU1F1 + tumor cells demonstrated intracellular protein trafficking and extracellular protein release. This aligned with the clinical manifestation of abnormally high secretion of certain hormones in the PIT1 lineage [ 5 ]. A recent study also supported these findings and demonstrated an inverse correlation between differentiation status and recurrence within the PIT1/TPIT lineage compared to the SF1 lineage [ 57 ].…”

Section: Discussionsupporting

confidence: 52%

“…This aligned with the clinical manifestation of abnormally high secretion of certain hormones in the PIT1 lineage [ 5 ]. A recent study also supported these findings and demonstrated an inverse correlation between differentiation status and recurrence within the PIT1/TPIT lineage compared to the SF1 lineage [ 57 ]. In particular, we combined 23 single-cell and 365 in-house bulk RNA-seq to reveal that all 3 PitNET subtypes have distinct immune-infiltrated patterns.…”

Section: Discussionsupporting

confidence: 52%

“…However, the specific function and heterogeneity of these immune cell subtypes in PitNETs remain poorly understood, which can help identify new therapeutic targets. Some studies have endeavored to characterize the immune microenvironment of PitNETs using immunohistochemistry (IHC) [ 16 ], flow cytometry (FC) [ 19 ], and RNA-seq (including both bulk RNA-seq and single-cell RNA-seq) [ 3 , 5 – 7 , 9 ]. Macrophages, a highly heterogeneous group of immune cells, have many functions, including phagocytosis, antigen presentation, cytokine production, and tissue remodeling [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

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Single-cell transcriptomics reveal distinct immune-infiltrating phenotypes and macrophage–tumor interaction axes among different lineages of pituitary neuroendocrine tumors

Lin,

Dai,

Han

et al. 2024

Genome Med

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Background Pituitary neuroendocrine tumors (PitNETs) are common gland neoplasms demonstrating distinctive transcription factors. Although the role of immune cells in PitNETs has been widely recognized, the precise immunological environment and its control over tumor cells are poorly understood. Methods The heterogeneity, spatial distribution, and clinical significance of macrophages in PitNETs were analyzed using single-cell RNA sequencing (scRNA-seq), bulk RNA-seq, spatial transcriptomics, immunohistochemistry, and multiplexed quantitative immunofluorescence (QIF). Cell viability, cell apoptosis assays, and in vivo subcutaneous xenograft experiments have confirmed that INHBA-ACVR1B influences the process of tumor cell apoptosis. Results The present study evaluated scRNA-seq data from 23 PitNET samples categorized into 3 primary lineages. The objective was to explore the diversity of tumors and the composition of immune cells across these lineages. Analyzed data from scRNA-seq and 365 bulk RNA sequencing samples conducted in-house revealed the presence of three unique subtypes of tumor immune microenvironment (TIME) in PitNETs. These subtypes were characterized by varying levels of immune infiltration, ranging from low to intermediate to high. In addition, the NR5A1 lineage is primarily associated with the subtype characterized by limited infiltration of immune cells. Tumor-associated macrophages (TAMs) expressing CX3CR1+, C1Q+, and GPNMB+ showed enhanced contact with tumor cells expressing NR5A1 + , TBX19+, and POU1F1+, respectively. This emphasizes the distinct interaction axes between TAMs and tumor cells based on their lineage. Moreover, the connection between CX3CR1+ macrophages and tumor cells via INHBA-ACVR1B regulates tumor cell apoptosis. Conclusions In summary, the different subtypes of TIME and the interaction between TAM and tumor cells offer valuable insights into the control of TIME that affects the development of PitNET. These findings can be utilized as prospective targets for therapeutic interventions.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 52%

Section: Discussionsupporting

confidence: 52%

Section: Introductionmentioning

confidence: 99%

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Single-cell transcriptomics reveal distinct immune-infiltrating phenotypes and macrophage–tumor interaction axes among different lineages of pituitary neuroendocrine tumors

Lin,

Dai,

Han

et al. 2024

Genome Med

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“…Taken together, our results were convincing the cultured hPASCs possessed the characteristics of TSCs. Recently single-cell sequencing of pituitary adenoma con rmed the presence of TSCs in the tumor, despite in a non-proliferative status [10]. We speculated other factors may be required to drive the hPASCs into the cell cycle and differentiation.…”

Section: Discussionmentioning

confidence: 85%

Transcriptional Profiling of Pituitary Adenoma Stem Cells: Unveiling the Pivotal Role of CXCR4 in Tumorigenesis and Clinical Applications

Yuan,

Li,

Sui

et al. 2023

Preprint

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Background Growth hormone-secreting pituitary adenoma (GHPA) is characterized by excessive growth hormone production and leads to clinical manifestations like acromegaly. The molecular intricacies underpinning the tumorigenesis of this neoplasm remain largely elusive, with tumor stem cells postulated to play a significant role. Method Human pituitary adenoma stem cells (hPASCs) were extracted and cultured from eight GHPA clinical samples. RNA-sequencing was performed to discern genetic disparities between hPASCs and matched bulk tumor samples. Primary clusters of protein-protein interaction network were mapped using MCODE plugin in Cytoscape. The functional role of CXCR4 was assessed by both siRNA and antagonist AMD3465 in GH3 cells or primary hPASCs. Seven GHPA patients received PET/CT scan using CXCR4-based tracer 68Ga-pentixafor. Results HPASC culture was established and verified. A total of 685 differentially expressed genes were identified between hPASC and bulk tumor samples. Four primary protein-protein interaction network clusters were predicted, each demonstrating distinct biological functions. CXCR4 knockdown significantly attenuated GH3 cell proliferation and the hormone production. CXCR4 antagonist AMD3465 markedly reduced cell proliferation during differentiation of hPASCs. PET/CT imaging showed 68Ga-pentixafor can be a superior tracer in the detection of GHPA in the patients. Conclusion This study delivers a comprehensive genetic profiling of hPASCs and substantiates the critical role of CXCR4 in tumorigenesis, highlighting its considerable diagnostic potential in the translational research.

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Erythropoietin-producing hepatocellular receptor B6 is highly expressed in non-functioning pituitary neuroendocrine tumors and its expression correlates with tumor size

Rubinfeld,

Cohen,

Bendavid

et al. 2024

Mol Biol Rep

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Background Erythropoietin-producing hepatocellular (EPH) receptors are the largest known family of receptor tyrosine kinases characterized in humans. These proteins are involved in tissue organization, synaptic plasticity, vascular development and the progression of various diseases including cancer. The Erythropoietin-producing hepatocellular receptor tyrosine kinase member EphB6 is a pseudokinase which has not attracted an equivalent amount of interest as its enzymatically-active counterparts. The aim of this study was to assess the expression of EphB6 in pituitary tumors. Methods and Results Human normal pituitaries and pituitary tumors were examined for EphB6 mRNA expression using real-time PCR and for EphB6 protein by immunohistochemistry and Western blotting. EphB6 was highly expressed in non-functioning pituitary neuroendocrine tumors (NF-PitNETs) versus the normal pituitary and GH-secreting PitNETs. EphB6 mRNA expression was correlated with tumor size. Conclusions Our results suggest EphB6 aberrant expression in NF-PitNETs. Future studies are warranted to determine the role and significance of EphB6 in NF-PitNETs tumorigenesis.

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Single-cell sequencing identifies differentiation-related markers for molecular classification and recurrence prediction of PitNET

Cited by 17 publications

References 85 publications

Single-cell transcriptomics reveal distinct immune-infiltrating phenotypes and macrophage–tumor interaction axes among different lineages of pituitary neuroendocrine tumors

Single-cell transcriptomics reveal distinct immune-infiltrating phenotypes and macrophage–tumor interaction axes among different lineages of pituitary neuroendocrine tumors

Transcriptional Profiling of Pituitary Adenoma Stem Cells: Unveiling the Pivotal Role of CXCR4 in Tumorigenesis and Clinical Applications

Erythropoietin-producing hepatocellular receptor B6 is highly expressed in non-functioning pituitary neuroendocrine tumors and its expression correlates with tumor size

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