Yin Zhao

Gemcitabine and cisplatin (GP) serve as first-line induction chemotherapy (IC) for nasopharyngeal carcinoma (NPC), yet predictive markers are lacking. Here we performed multi-omics profiling, including proteomics, phosphoproteomics, genomics and transcriptomics, on 240 patients with NPC who were receiving GP-IC or concurrent chemoradiotherapy (CCRT) alone. Through multi-omic integration, we identified three proteomic subtypes with distinct therapeutic vulnerabilities. The S1 subtype showed a predominant interferon-γ response and had favorable outcomes with CCRT alone. The S2 subtype featured copy-number-driven cell cycle activation, deriving benefits from GP-IC. The immune-exhausted S3 subtype exhibited high IgA⁺ plasma cell infiltration and was resistant to GP-IC but responded to anti-PD-1 therapy. Single-cell RNA sequencing confirmed interaction between IgA⁺ plasma cells and CD8⁺ T cells in nonresponders. Validation from three phase III trials and spatial analyses demonstrated that high IgA⁺ plasma cell infiltration predicted GP-IC resistance but benefited from anti-PD-1 therapy. This study delineates a subtype-specific landscape of GP-IC response and may inform personalized treatment in NPC.

Supplementary Table from CircIPO7 Promotes Nasopharyngeal Carcinoma Metastasis and Cisplatin Chemoresistance by Facilitating YBX1 Nuclear Localization

Supplementary Figure from CircIPO7 Promotes Nasopharyngeal Carcinoma Metastasis and Cisplatin Chemoresistance by Facilitating YBX1 Nuclear Localization

Purpose:Cisplatin-based chemotherapy effectively improves the distant-metastasis control in nasopharyngeal carcinoma (NPC), but approximately 30% of patients develop treatment failure due to chemoresistance. However, the underlying mechanisms remain poorly understood.Experimental Design:Circular RNA (circRNA) sequencing data were used to identify metastasis-specific circRNAs and the expression of circIPO7 was validated in NPC tissues as well as NPC cell lines by qRT-PCR. The whole transcriptional profile upon circIPO7 knockdown was applied to explore the biological function and regulatory mechanism, which were further confirmed by in vitro and in vivo metastasis/chemosensitivity assays. We also evaluated the value of circIPO7 expression in predicting NPC metastasis and cisplatin chemoresistance by analyzing a cohort of 183 NPC patients.Results:In this study, circIPO7, a novel circRNA, is found to be specifically overexpressed in NPC patients with distant metastasis. Knockdown of circIPO7 in NPC cells suppresses their metastasis and increases sensitivity to cisplatin treatment in vitro and in vivo. Mechanistically, circIPO7 binds to Y-box binding protein-1 (YBX1) protein in the cytoplasm and facilitates its phosphorylation at serine 102 (p-YBX1S102) by the kinase AKT, which further promotes YBX1 nuclear translocation and activates FGFR1, TNC, and NTRK1 transcription. Clinically, higher circIPO7 expression indicates unfavorable distant metastasis-free survival in NPC patients given cisplatin-based chemotherapy.Conclusions:Altogether, this study identifies oncogenic circIPO7 as a prognostic marker after cisplatin-based chemotherapy and as a potential therapeutic target for overcoming metastasis and chemoresistance in NPC.

Supplementary Figure from CircIPO7 Promotes Nasopharyngeal Carcinoma Metastasis and Cisplatin Chemoresistance by Facilitating YBX1 Nuclear Localization

Supplementary Figure from CircIPO7 Promotes Nasopharyngeal Carcinoma Metastasis and Cisplatin Chemoresistance by Facilitating YBX1 Nuclear Localization

Supplementary Figure from CircIPO7 Promotes Nasopharyngeal Carcinoma Metastasis and Cisplatin Chemoresistance by Facilitating YBX1 Nuclear Localization

Supplementary Table from CircIPO7 Promotes Nasopharyngeal Carcinoma Metastasis and Cisplatin Chemoresistance by Facilitating YBX1 Nuclear Localization

Supplementary Figure from CircIPO7 Promotes Nasopharyngeal Carcinoma Metastasis and Cisplatin Chemoresistance by Facilitating YBX1 Nuclear Localization

Supplementary Figure from CircIPO7 Promotes Nasopharyngeal Carcinoma Metastasis and Cisplatin Chemoresistance by Facilitating YBX1 Nuclear Localization