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Multi-omics analysis and experiments uncover the link between cancer intrinsic drivers, stemness, and immunotherapy in ovarian cancer with validation in a pan-cancer census

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机构: [1]Univ Elect Sci & Technol China, Sichuan Prov Peoples Hosp, Sch Med, Dept Obstet & Gynecol, Chengdu, Sichuan, Peoples R China [2]Fudan Univ, Huashan Hosp, Dept Oncol, Shanghai, Peoples R China [3]Binzhou Med Univ, Binzhou Med Univ Hosp, Dept Reprod Med, Binzhou, Shandong, Peoples R China [4]Binzhou Med Univ, Binzhou Med Univ Hosp, Med Res Ctr, Binzhou, Shandong, Peoples R China [5]Binzhou Med Univ, Binzhou Med Univ Hosp, Dept Pathol, Binzhou, Shandong, Peoples R China [6]Meishan City Peoples Hosp, Meishan, Sichuan, Peoples R China [7]Binzhou Med Univ Hosp, Dept Tradit Chinese Med, Binzhou, Shandong, Peoples R China [8]Binzhou Med Univ Hosp, Dept Intervent Vasc Surg, Binzhou, Shandong, Peoples R China [9]Huashan Hosp Fudan Univ, Inst Intergrated Tradit Chinese & Western Med, Huashan Hosp, Shanghai, Peoples R China
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关键词: cancer stemness intrinsic heterogeneity immunotherapy therapy CSE1L ovarian cancer

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Background Although immune checkpoint inhibitors (ICIs) represent a substantial breakthrough in cancer treatment, it is crucial to acknowledge that their efficacy is limited to a subset of patients. The heterogeneity and stemness of cancer render its response to immunotherapy variable, warranting the identification of robust biomarkers for evaluation.Methods Publicly available Ovarian Cancer (OV) single-cell RNA (scRNA) sequence dataset was collected and analyzed to elucidate the intrinsic driver gene of OV cancer cells. Through genome-scale CRISPR screening of RNA sequencing data from Project Achilles, essential genes specific to OV were identified. A novel cancer stem cell index (CSCI) was developed and validated using multiple advanced algorithms and large-scale datasets, as well as corresponding clinical features, including 14 OV transcriptomic datasets, 7 pan-cancer ICI transcriptomic cohorts and one melanoma scRNA dataset derived from PD-1 treated patients.Results Chromosomal 20q gain, 8q gain, and 5q loss have been identified as ovarian cancer-specific driving variations. By analyzing large-scale datasets of ovarian cancer transcriptomics, including scRNA and CRISPR cell line datasets, we have identified a gene set that influences tumor intrinsic drivers and stemness properties. We then developed the CSCI to predict the prognosis and response to immunotherapy in ovarian cancer patients using advanced machine learning algorithms. When applied to PD1/PD-L1 ICI transcriptomic cohorts, CSCI consistently and accurately predicts tumor progression and immunotherapy benefits, with a mean AUC greater than 0.8. Notably, compared to previously established signatures, CSCI demonstrates better predictive performance across multiple ovarian cancer datasets. Intriguingly, we discovered that amplification of CSE1L enhances the stemness of tumor-initiating cells, facilitates angiogenesis, and the formation of ovarian cancer, which can serve as a potential therapeutic target. Finally, experiments validated that CSE1L promotes progression, migration, and proliferation of ovarian cancer.Conclusions Our study has uncovered a robust correlation between variations in cancer intrinsic drivers and stemness, as well as resistance to immunotherapy. This finding provides valuable insights for potential strategies to overcome immune resistance by targeting genes associated with stemness.

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基金编号: 82200981 ZR2023MH222 ZR2022QH192 ZR2023QH030 tsqn202312384 2023YFS0039

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大类 | 2 区 医学
小类 | 2 区 免疫学
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大类 | 2 区 医学
小类 | 2 区 免疫学
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Q1 IMMUNOLOGY
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Q1 IMMUNOLOGY

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第一作者机构: [1]Univ Elect Sci & Technol China, Sichuan Prov Peoples Hosp, Sch Med, Dept Obstet & Gynecol, Chengdu, Sichuan, Peoples R China
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