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

被引：0

作者：

Tao, Mei ^{[1
]}

Wu, Shuping ^{[2
]}

Liu, Yimeng ^{[1
]}

Ruan, Xianhui ^{[1
]}

Zhang, Wei ^{[1
,3
]}

Luo, Wei ^{[1
]}

Yu, Jialong ^{[1
]}

Zeng, Yu ^{[1
]}

Ning, Junya ^{[1
,4
]}

Zheng, Xiangqian ^{[1
]}

Gao, Ming ^{[1
,3
,4
]}

机构：

[1] Tianjin Med Univ, Dept Thyroid & Neck Tumor, Key Lab Canc Prevent & Therapy, Natl Clin Res Ctr Canc,Tianjins Clin Res Ctr Canc,, Tianjin 300060, Peoples R China

[2] Fujian Med Univ, Fujian Canc Hosp, Clin Oncol Sch, Dept Head & Neck Surg, 420 Fuma Rd, Fuzhou 350014, Fujian, Peoples R China

[3] Tianjin Union Med Ctr, Tianjin Key Lab Gen Surg Construct, Tianjin 300121, Peoples R China

[4] Tianjin Union Med Ctr, Dept Thyroid & Breast Surg, Tianjin 300121, Peoples R China

来源：

ENDOCRINE | 2025年

基金：

中国国家自然科学基金;

关键词：

Gene expression programs; Consensus nonnegative matrix factorization; ELF3; Drug sensitivity; Lymph node metastasis; HETEROGENEITY; 17-ALLYLAMINO-17-DEMETHOXYGELDANAMYCIN; REGULATORS; EVOLUTION;

D O I：

10.1007/s12020-025-04205-y

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

BackgroundAdvanced papillary thyroid carcinoma (PTC) exhibits significant heterogeneity. Understanding the gene expression programs underlying tumor heterogeneity is crucial for improving diagnostic and therapeutic strategies.MethodsWe 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.ResultsWe 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.ConclusionsThis 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.

引用

页数：22