Molecular landscapes and mechanisms of squamous bladder cancer

鳞状膀胱癌的分子景观和机制

• 批准号: 452515298
• 负责人: Professorin Dr. Nadine Gaisa
• 金额: --
• 依托单位: Institut für Pathologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/452515298?language=en
• 关键词: Molecular; landscapes; mechanisms; squamous; bladder

Pure squamous cell carcinoma (SCC) of the urinary bladder is an infrequent diagnosis, but it is associated with unfavorable prognosis and limited options for adjuvant therapy. SCC are believed to evolve from a dynamic phase transition of microscopically recognizable precursor lesions referred to as squamous metaplasia and dysplasia. However, the molecular mechanisms facilitating the aberrant differentiation of squamous epithelial cells within the urothelium and subsequent cancerogenesis are poorly understood. Despite high-throughput sequencing approaches and detailed understanding of molecular landscapes across different cancer types, genome-wide data of pure SCC of the urinary bladder have not yet been collected. In particular, omics data of precancerous lesions are completely missing. Therefore, we have established a cohort of fresh frozen tissues from completely embedded cystectomy specimens comprising patient matched normal urothelium, squamous metaplasia, partly dysplasia and concomitant SCC lesions in order to decipher the molecular mechanisms of the phase transition from urothelium to squamous metaplasia, dysplasia and SCC. We aim to perform an integrative genomic (Whole Exome Sequencing), transcriptomic (Affymetrix arrays) and epigenomic (Infinium MethylationEPIC BeadChip) analysis involving different steps of bioinformatics and experimental analyses: 1) By individual and multidirectional analyses we will identify phase transition specific co-operative contributions of DNA mechanisms (genomic, epigenomic) which could explain differential gene expression involved in multistep phase transition of benign to malignant squamous differentiation. 2) A strict bioinformatics based evaluation of regulatory mechanisms will reduce identified (epi-)genetic regulatory candidates which will also be further cross-validated by publicly available datasets (e.g. TCGA) and literature to reveal candidate genes and/or complex signatures as well as signaling pathways of clinical and functional significance. 3) Further validation of selected candidates in independent FFPE cohorts and cell line models based on RT-PCR, pyrosequencing or western blots will further strengthen or dismiss candidates. 4) Additionally, a high risk integrative bioinformatics approach will be conducted with Prof. Schuppert at the Institute for Computational Biomedicine and Prof. Wagner at the Departenment of Stem Cell Biology and Cellular Engineering. With this study, we will provide comprehensive novel insights into the poorly understood multistep carcinogenesis of squamous bladder cancer and our data will provide the basis for further in vitro and in vivo models of putative key regulatory players.

单纯膀胱鳞状细胞癌(SCC)是一种罕见的诊断，但它与不良预后和有限的辅助治疗选择有关。鳞状细胞癌被认为是从显微镜下可识别的称为鳞状化生和异型增生的前体病变的动态相变演变而来的。然而，促进尿路上皮内鳞状上皮细胞异常分化和随后的癌变的分子机制却知之甚少。尽管高通量测序方法和对不同癌症类型的分子景观的详细了解，纯膀胱SCC的全基因组数据尚未收集。特别是，癌前病变的组学数据完全缺失。因此，我们从完全包埋的膀胱切除标本中建立了新鲜冰冻组织队列，包括患者匹配的正常尿路上皮、鳞状化生、部分不典型增生和伴发的鳞状细胞癌病变，以破译从尿路上皮到鳞状化生、不典型增生和鳞状细胞癌相变的分子机制。我们的目标是进行整合的基因组(全外显子组测序)、转录(Affymetrix阵列)和表观基因组(Infinium MethylationEPIC BeadChip)分析，涉及生物信息学的不同步骤和实验分析：1)通过单独和多方向的分析，我们将识别DNA机制(基因组、表观基因组)的特定合作贡献，这可以解释良性到恶性鳞状细胞分化多步骤相变过程中的差异基因表达。2)严格基于生物信息学的调控机制评估将减少已识别的(表观)基因调控候选基因，这也将通过公开可用的数据集(如TCGA)和文献进一步交叉验证，以揭示候选基因和/或复杂签名以及具有临床和功能意义的信号通路。3)在基于RT-PCR、焦磷酸测序或蛋白质印迹的独立FFPE队列和细胞系模型中进一步验证选定的候选对象将进一步加强或排除候选对象。4)此外，还将与计算生物医学研究所的Schuppert教授和干细胞生物学和细胞工程系的Wagner教授一起进行高风险综合生物信息学方法。通过这项研究，我们将为了解鳞状膀胱癌的多步骤致癌机制提供全面的新见解，我们的数据将为进一步建立可能的关键调控因子的体外和体内模型提供基础。