Huai-Wu Lu

HNRNPC mediates lymphatic metastasis of cervical cancer through m6A-dependent alternative splicing of FOXM1

AbstractCervical cancer (CCa) patients with lymph node (LN) metastasis face poor prognoses and have limited treatment options. Aberrant N6-methyladenosine (m6A) modification of RNAs are known to promote tumor metastasis, but their role in CCa remains unclear. Our study reveals that HNRNPC, an alternative splicing (AS) factor and m6A reader, increases tumor-related variants through m6A-dependent manner, thereby promoting lymphatic metastasis in CCa. We found that HNRNPC overexpression correlates with lymphatic metastasis and poorer prognoses in CCa patients. Functionally, knocking down HNRNPC markedly inhibited the migration and invasion of several CCa cell lines, while supplementing HNRNPC restored the malignant phenotypes of these cells. Mechanistically, HNRNPC regulates exon skipping of FOXM1 by binding to its m6A-modified motif. Mutating the m6A site on FOXM1 weakened the interaction between HNRNPC and FOXM1 pre-RNA, leading to a reduction in the metastasis-related FOXM1-S variant. In conclusion, our findings demonstrate that m6A-dependent alternative splicing mediated by HNRNPC is essential for lymphatic metastasis in CCa, potentially providing novel clinical markers and therapeutic strategies for patients with advanced CCa.

Molecular and Immune Correlates of Response to First-Line De-escalated Chemotherapy plus Penpulimab and Anlotinib in Advanced Cervical Cancer

Abstract The standard of care for advanced cervical cancer includes chemotherapy, antiangiogenic, and/or immune checkpoint blockade regimens. Although effective, it leads to pleiotropic side effects. Deescalation chemotherapy together with immunotargeted therapies has been proven effective and less toxic in other cancers. In this study, we conducted a multicenter, single-arm, phase II study of first-line deescalated platinum-based chemotherapy plus anlotinib and penpulimab, followed by maintenance therapy solely with anlotinib and penpulimab in patients with PD-L1–positive, persistent, recurrent, or metastatic cervical cancer. Of 32 efficacy-evaluable patients, 30 (93.8%, 95% confidence interval, 79.2%–99.2%) had an investigator-confirmed objective response. Single-nucleus RNA sequencing implied enhanced chemotaxis and proliferative activity of tumor-infiltrating T cells, and activated germinal center B cells portended optimal treatment response. Patients with a high tertiary lymphoid structure-to-tumor area ratio exhibited better survival. Our findings lay the groundwork for the feasibility of first-line de-escalated chemotherapy plus anlotinib and penpulimab in patients with metastatic, persistent, or recurrent cervical cancer. Significance: We recruited 34 patients with advanced cervical cancer receiving two cycles of platinum-based chemotherapy plus anlotinib and penpulimab, followed by maintenance therapy solely with anlotinib and penpulimab, and showed safety and efficacy of this deescalation regimen. This work highlights the potential for personalized treatment strategies and feasibility of reduced-toxicity regimens.

Comprehensive clinical analysis of gastric-type endocervical adenocarcinoma: a real-world multicenter study

Gastric-type endocervical adenocarcinoma (G-EAC) is a rare malignancy, and its clinicopathological characteristics remain poorly defined. This study aimed to evaluate the real-world features, treatment patterns, and outcomes of patients with G-EAC. Clinical data from 124 patients diagnosed with G-EAC between 2012 and 2024 across four tertiary hospitals in China were retrospectively analyzed. Clinicopathological features, therapeutic approaches, and survival outcomes were assessed. Overall survival (OS) was the primary endpoint. Kaplan-Meier and Cox regression analyses were performed to identify prognostic factors. The median diagnostic age was 55 years (range, 33-82). At presentation, 62.1% of patients had invasion or metastasis, most commonly lymphovascular (47.6%). Surgery was performed in 81.5% of cases, and 84.7% received chemotherapy, primarily platinum-based (81.5%). Radiotherapy was administered to 69.4%. The 1-, 3-, and 5-year OS rates were 78.6%, 54.8%, and 46.1%, respectively. Older age (≥65 years; HR, 4.71; 95% CI, 1.52-14.58; G-EAC exhibits aggressive behavior and unfavorable prognosis, with a 5-year OS of 46.1%. Multimodal treatment, particularly surgery combined with chemotherapy, remains the cornerstone of management and may improve survival. Prospective multicenter studies are warranted to further define optimal therapeutic strategies for this rare entity.

A gene-based predictive model for lymph node metastasis in cervical cancer: superior performance over imaging techniques

Abstract Objective Lymph node metastasis (LNM) critically impacts the prognosis and treatment decisions of cervical cancer patients. The accuracy and sensitivity of current imaging techniques, such as CT and MRI, are limited in assessing lymph node status. This study aims to develop a more accurate and efficient method for predicting LNM. Methods Three independent cohorts were merged and divided into training and internal validation groups, with our cohort and those from other centers serving as external validation. A predictive model for LNM in cervical cancer was established using the LASSO regression and multivariate logistic regression. The diagnostic performance of the predictive model was compared with that of CT/MRI in terms of accuracy, sensitivity, specificity, and AUC. Results Using RNA-seq data, four independent predictive genes (MAPT, EPB41L1, ACSL5, and PRPF4B) were identified through LASSO regression and multivariate logistic regression, and a predictive model was constructed to calculate the LNM risk score. Compared with CT/MRI, the model demonstrated higher diagnostic efficiency, with an accuracy of 0.840 and sensitivity of 0.804, compared to CT/MRI’s accuracy of 0.713 and sensitivity of 0.587. The predictive model corrected 81% of misdiagnoses by CT/MRI, demonstrating significant improvements in accuracy and sensitivity. Conclusion The predictive model developed in this study, based on gene expression data, significantly improves the preoperative assessment accuracy of LNM in cervical cancer. Compared to traditional imaging techniques, this model shows superior sensitivity and accuracy. This study provides a robust foundation for developing precise diagnostic tools, paving the way for future clinical applications in individualized treatment planning.

Single-cell and spatial transcriptomic profiling reveals distinct tumor microenvironment dynamics in cervical adenocarcinoma and squamous cell carcinoma

Cervical cancer (CC), a leading cause of cancer-related deaths among women worldwide, is primarily driven by high-risk human papillomavirus (HPV) infections and comprises two major histological subtypes: adenocarcinoma (AC) and squamous cell carcinoma (SCC). Despite advances in prevention and treatment, the molecular and cellular heterogeneity of these subtypes poses significant challenges to achieving optimal clinical outcomes. Here, we integrate single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) to dissect the cellular and spatial heterogeneity of AC and SCC, uncovering distinct tumor microenvironment (TME) dynamics that underlie their divergent clinical behaviors. Our scRNA-seq analysis reveals that AC is enriched in epithelial cells, while SCC exhibits a more immunogenic TME with elevated plasma cells and NK/T cells. Spatial transcriptomics further highlights robust interactions between CD8 + T cells and epithelial subtypes in SCC, contrasting with the stromal-rich, immune-cold phenotype of AC. We identify subtype-specific immune and stromal features, including ICOS+ Tregs, IDO1+ cancer-associated fibroblasts (CAFs), and PLVAP+ endothelial cells, which may drive immune evasion, angiogenesis, and metastasis. These findings provide a comprehensive framework for understanding CC heterogeneity and offer actionable insights for developing subtype-specific therapeutic strategies, such as combining immune checkpoint inhibitors with stromal-targeting agents. This study underscores the potential of spatial multi-omics technologies to advance precision oncology and improve outcomes for cervical cancer patients.