基于液-液相分离及其与膀胱癌免疫表型相互作用的分子亚型鉴定。
Identification of molecular subtypes based on liquid-liquid phase separation and cross-talk with immunological phenotype in bladder cancer.
机构信息
Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China.
Department of Biological Repositories, Cancer Precision Diagnosis and Treatment and Translational Medicine Hubei Engineering Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China.
出版信息
Front Immunol. 2022 Nov 28;13:1059568. doi: 10.3389/fimmu.2022.1059568. eCollection 2022.
BACKGROUND
Mounting evidence has demonstrated that an imbalance in liquid-liquid phase separation (LLPS) can induce alteration in the spatiotemporal coordination of biomolecular condensates, which plays a role in carcinogenesis and cachexia. However, the role of LLPS in the occurrence and progression of bladder cancer (BLCA) remains to be elucidated. Identifying the role of LLPS in carcinogenesis may aid in cancer therapeutics.
METHODS
A total of 1,351 BLCA samples from six cohorts were retrieved from publicly available databases like The Cancer Genome Atlas, Gene Expression Omnibus, and ArrayExpress. The samples were divided into three distinct clusters, and their multi-dimensional heterogeneities were explored. The LLPS patterns of all patients were determined based on the LLPS-related risk score (LLPSRS), and its multifaceted landscape was depicted and experimentally validated at the multi-omics level. Finally, a cytotoxicity-related and LLPSRS-based classifier was established to predict the patient's response to immune checkpoint blockade (ICB) treatment.
RESULTS
Three LLPS-related subtypes were identified and validated. The differences in prognosis, tumor microenvironment (TME) features, cancer hallmarks, and certain signatures of the three LLPS-related subtypes were validated. LLPSRS was calculated, which could be used as a prognostic biomarker. A close correlation was observed between clinicopathological features, genomic variations, biological mechanisms, immune infiltration in TME, chemosensitivity, and LLPSRS. Furthermore, our classifier could effectively predict immunotherapy response in patients with BLCA.
CONCLUSIONS
Our study identified a novel categorization of BLCA patients based on LLPS. The LLPSRS could predict the prognosis of patients and aid in designing personalized medicine. Further, our binary classifier could effectively predict patients' sensitivity to immunotherapy.
背景
越来越多的证据表明，液-液相分离（LLPS）的失衡会导致生物分子凝聚物的时空协调改变，这在致癌和恶病质中发挥作用。然而，LLPS 在膀胱癌（BLCA）的发生和进展中的作用仍有待阐明。确定 LLPS 在致癌作用中的作用可能有助于癌症治疗。
方法
从 The Cancer Genome Atlas、Gene Expression Omnibus 和 ArrayExpress 等公开数据库中检索了 6 个队列中总共 1351 个 BLCA 样本。将这些样本分为三个不同的簇，并对其多维异质性进行了探索。根据与 LLPS 相关的风险评分（LLPSRS）确定了所有患者的 LLPS 模式，并在多组学水平上对其多方面的图谱进行了描绘和实验验证。最后，建立了一个基于细胞毒性相关和 LLPSRS 的分类器，以预测患者对免疫检查点阻断（ICB）治疗的反应。
结果
确定并验证了三种与 LLPS 相关的亚型。验证了三种与 LLPS 相关的亚型之间在预后、肿瘤微环境（TME）特征、癌症标志和某些特征上的差异。计算了 LLPSRS，可以作为预后生物标志物。观察到 LLPSRS 与临床病理特征、基因组变异、生物学机制、TME 中的免疫浸润、化疗敏感性密切相关。此外，我们的分类器可以有效地预测 BLCA 患者的免疫治疗反应。
结论
本研究根据 LLPS 对 BLCA 患者进行了新的分类。LLPSRS 可预测患者的预后，并有助于制定个体化治疗方案。此外，我们的二进制分类器可以有效地预测患者对免疫治疗的敏感性。
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