LAPTM5 drives omental metastasis in high-grade serous ovarian cancer via TGF-β/Smad-mediated epithelial plasticity.

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.