Journal of translational medicine · 2025
LAPTM5 drives omental metastasis in high-grade serous ovarian cancer via TGF-β/Smad-mediated epithelial plasticity.
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Gao Yan, Li Jie, Han Xiaoyang, Li Zhefeng, Cheng Jin, Hou Lisha, Jiang Mei, Yin Chenghong, Yue Wentao
Аннотация
BACKGROUND: High-grade serous ovarian cancer (HGSOC) is an aggressive gynecological malignancy marked by widespread metastasis, most notably to the omentum. However, the molecular mechanisms driving this process remain poorly understood.
METHODS: We present an integrated analysis of single-cell RNA sequencing (scRNA-seq) data from normal ovaries, primary tumors, and omental metastases to generate a high-resolution cellular landscape of HGSOC. LAPTM5 expression was examined by immunohistochemistry, immunofluorescence, qPCR, western blotting, and analyses of TCGA datasets. Functional assays including Transwell migration/invasion, wound healing, flow cytometry, single-nucleotide variant (SNV) and alternative splicing (AS) analysis were performed after LAPTM5 knockdown. The proteins expression involved in epithelial-mesenchymal transition (EMT) and TGF-β mediated signaling pathways was verified by qPCR and western blotting. The critical role of LAPTM5 on metastasis in vivo was detected by the tumor-bearing mice model.
RESULTS: We identified a metastasis-associated epithelial subcluster characterized by immune suppression and poor prognosis, with LAPTM5 emerging as a defining marker. Functional assays revealed that LAPTM5 silencing significantly impaired HGSOC cell migration, invasion, and epithelial-mesenchymal transition (EMT) in vitro, and reduced metastatic burden in vivo. Mechanistically, LAPTM5 activates the TGF-β/Smad signaling pathway, promoting EMT and facilitating omental metastasis. Intriguingly, LAPTM5 knockdown led to reduced single-nucleotide variant (SNV) accumulation and alternative splicing (AS) events, thereby decreasing the expression of metastasis-associated genes.
CONCLUSIONS: These findings identify LAPTM5 as a key regulator of TGF-β/Smad-driven epithelial plasticity and omental dissemination in HGSOC, positioning it as both a prognostic biomarker and a potential therapeutic target for advanced-stage disease.
METHODS: We present an integrated analysis of single-cell RNA sequencing (scRNA-seq) data from normal ovaries, primary tumors, and omental metastases to generate a high-resolution cellular landscape of HGSOC. LAPTM5 expression was examined by immunohistochemistry, immunofluorescence, qPCR, western blotting, and analyses of TCGA datasets. Functional assays including Transwell migration/invasion, wound healing, flow cytometry, single-nucleotide variant (SNV) and alternative splicing (AS) analysis were performed after LAPTM5 knockdown. The proteins expression involved in epithelial-mesenchymal transition (EMT) and TGF-β mediated signaling pathways was verified by qPCR and western blotting. The critical role of LAPTM5 on metastasis in vivo was detected by the tumor-bearing mice model.
RESULTS: We identified a metastasis-associated epithelial subcluster characterized by immune suppression and poor prognosis, with LAPTM5 emerging as a defining marker. Functional assays revealed that LAPTM5 silencing significantly impaired HGSOC cell migration, invasion, and epithelial-mesenchymal transition (EMT) in vitro, and reduced metastatic burden in vivo. Mechanistically, LAPTM5 activates the TGF-β/Smad signaling pathway, promoting EMT and facilitating omental metastasis. Intriguingly, LAPTM5 knockdown led to reduced single-nucleotide variant (SNV) accumulation and alternative splicing (AS) events, thereby decreasing the expression of metastasis-associated genes.
CONCLUSIONS: These findings identify LAPTM5 as a key regulator of TGF-β/Smad-driven epithelial plasticity and omental dissemination in HGSOC, positioning it as both a prognostic biomarker and a potential therapeutic target for advanced-stage disease.
Предметные рубрики MeSH
FemaleOmentumHumansTransforming Growth Factor betaEpithelial-Mesenchymal TransitionAnimalsCell Line, TumorNeoplasm MetastasisOvarian NeoplasmsSmad ProteinsMembrane ProteinsCell MovementSignal TransductionNeoplasm GradingMiceGene Expression Regulation, NeoplasticCell PlasticityCystadenocarcinoma, SerousAlternative SplicingNeoplasm Invasiveness