Consensus nonnegative matrix factorization reveals metastatic gene expression program and identifies E74-like ETS transcription factor 3 confers to the lymph nodes metastasis in papillary thyroid cancer.

IF 3 3区医学 Q2 ENDOCRINOLOGY & METABOLISM

Endocrine Pub Date : 2025-03-06 DOI:10.1007/s12020-025-04205-y

Mei Tao, Shuping Wu, Yimeng Liu, Xianhui Ruan, Wei Zhang, Wei Luo, Jialong Yu, Yu Zeng, Junya Ning, Xiangqian Zheng, Ming Gao

{"title":"Consensus nonnegative matrix factorization reveals metastatic gene expression program and identifies E74-like ETS transcription factor 3 confers to the lymph nodes metastasis in papillary thyroid cancer.","authors":"Mei Tao, Shuping Wu, Yimeng Liu, Xianhui Ruan, Wei Zhang, Wei Luo, Jialong Yu, Yu Zeng, Junya Ning, Xiangqian Zheng, Ming Gao","doi":"10.1007/s12020-025-04205-y","DOIUrl":null,"url":null,"abstract":"Background: Advanced papillary thyroid carcinoma (PTC) exhibits significant heterogeneity. Understanding the gene expression programs underlying tumor heterogeneity is crucial for improving diagnostic and therapeutic strategies.Methods: We integrated single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data to explore transcriptional heterogeneity in PTC. Using consensus nonnegative matrix factorization (cNMF), we identified gene expression programs (GEPs) within malignant cells. A machine learning framework was applied to establish a lymph node metastasis (LNM) signature. Functional validation of key genes was performed through in vitro experiments, and drug screening was conducted to identify potential therapeutic candidates.Results: We identified an epithelial-mesenchymal transition (EMT)-related gene expression program, GEP3, which was strongly associated with LNM and poor clinical outcomes in PTC. Within the GEP3high subcluster, we pinpointed ELF3 as a hub gene driving tumor invasiveness and angiogenesis. Notably, BRAF V600E mutations were associated with higher GEP3 expression levels, indicating that ELF3 may be a pivotal marker for aggressive disease progression, especially in BRAF-mutant PTC. Functional assays confirmed that ELF3 knockdown suppressed EMT and angiogenesis, reducing PTC cell migration and invasion. Regardless of whether they are positive or negative for BRAF V600E mutations, showed increased sensitivity to vemurafenib in higher ELF3 expression group.Conclusions: This study highlights the critical role of GEP and ELF3 in driving PTC progression and metastasis. Drug screening revealed that tanespimycin and vemurafenib were effective in targeting GEP3high cells, offering therapeutic potential for aggressive PTC. These insights advance precision strategies for managing metastatic and heterogeneous PTC by targeting ELF3-driven pathways.","PeriodicalId":49211,"journal":{"name":"Endocrine","volume":" ","pages":""},"PeriodicalIF":3.0000,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Endocrine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s12020-025-04205-y","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}

引用次数: 0

Abstract

Background: Advanced papillary thyroid carcinoma (PTC) exhibits significant heterogeneity. Understanding the gene expression programs underlying tumor heterogeneity is crucial for improving diagnostic and therapeutic strategies.

Methods: We integrated single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data to explore transcriptional heterogeneity in PTC. Using consensus nonnegative matrix factorization (cNMF), we identified gene expression programs (GEPs) within malignant cells. A machine learning framework was applied to establish a lymph node metastasis (LNM) signature. Functional validation of key genes was performed through in vitro experiments, and drug screening was conducted to identify potential therapeutic candidates.

Results: We identified an epithelial-mesenchymal transition (EMT)-related gene expression program, GEP3, which was strongly associated with LNM and poor clinical outcomes in PTC. Within the GEP3^high subcluster, we pinpointed ELF3 as a hub gene driving tumor invasiveness and angiogenesis. Notably, BRAF V600E mutations were associated with higher GEP3 expression levels, indicating that ELF3 may be a pivotal marker for aggressive disease progression, especially in BRAF-mutant PTC. Functional assays confirmed that ELF3 knockdown suppressed EMT and angiogenesis, reducing PTC cell migration and invasion. Regardless of whether they are positive or negative for BRAF V600E mutations, showed increased sensitivity to vemurafenib in higher ELF3 expression group.

Conclusions: This study highlights the critical role of GEP and ELF3 in driving PTC progression and metastasis. Drug screening revealed that tanespimycin and vemurafenib were effective in targeting GEP3^high cells, offering therapeutic potential for aggressive PTC. These insights advance precision strategies for managing metastatic and heterogeneous PTC by targeting ELF3-driven pathways.

查看原文本刊更多论文

求助全文

约1分钟内获得全文求助全文

来源期刊

Endocrine ENDOCRINOLOGY & METABOLISM-

CiteScore

6.50

自引率

5.40%

发文量

295

审稿时长

1.5 months

期刊介绍： Well-established as a major journal in today’s rapidly advancing experimental and clinical research areas, Endocrine publishes original articles devoted to basic (including molecular, cellular and physiological studies), translational and clinical research in all the different fields of endocrinology and metabolism. Articles will be accepted based on peer-reviews, priority, and editorial decision. Invited reviews, mini-reviews and viewpoints on relevant pathophysiological and clinical topics, as well as Editorials on articles appearing in the Journal, are published. Unsolicited Editorials will be evaluated by the editorial team. Outcomes of scientific meetings, as well as guidelines and position statements, may be submitted. The Journal also considers special feature articles in the field of endocrine genetics and epigenetics, as well as articles devoted to novel methods and techniques in endocrinology. Endocrine covers controversial, clinical endocrine issues. Meta-analyses on endocrine and metabolic topics are also accepted. Descriptions of single clinical cases and/or small patients studies are not published unless of exceptional interest. However, reports of novel imaging studies and endocrine side effects in single patients may be considered. Research letters and letters to the editor related or unrelated to recently published articles can be submitted. Endocrine covers leading topics in endocrinology such as neuroendocrinology, pituitary and hypothalamic peptides, thyroid physiological and clinical aspects, bone and mineral metabolism and osteoporosis, obesity, lipid and energy metabolism and food intake control, insulin, Type 1 and Type 2 diabetes, hormones of male and female reproduction, adrenal diseases pediatric and geriatric endocrinology, endocrine hypertension and endocrine oncology.