Investigation of the role of epithelial-mesenchymal plasticity in renal cell carcinoma

上皮间质可塑性在肾细胞癌中作用的研究

• 批准号: 10178258
• 负责人: Giannicola Genovese
• 金额: $ 59.13万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10178258
• 关键词: Address; Aggressive behavior; Automobile Driving; Basic Science; Behavior; Biological Markers; Biological Models; Biology; Cancer Biology; Cancer Patient; Cells; Chromosomal Instability; Chromosome abnormality; Clinic; Clinical; Clinical Course of Disease; Clinical Oncology; Clonal Evolution; Clonal Expansion; Clustered Regularly Interspaced Short Palindromic Repeats; Communities; Conflict (Psychology); Dependence; Development; Disease; Disease Progression; Drug Targeting; Drug resistance; Ecosystem; Epigenetic Process; Epithelial; Epithelial Cells; Event; Evolution; Face; Genetic; Genetic Engineering; Genomic approach; Genomics; Goals; Heterogeneity; Human; Immunotherapy; Intervention; Investigation; Knowledge; Label; Light; Malignant - descriptor; Malignant Neoplasms; Mesenchymal; Mesenchymal Differentiation; Metaplasia; Mission; Modeling; Modernization; Molecular; Molecular Genetics; Mosaicism; Neurofibromin 2; Oncologist; Outcome; Pathologic; Patients; Pattern; Pharmacology; Phenotype; Physiology; Population; Population Dynamics; Primary Neoplasm; Recurrence; Regimen; Renal Cell Carcinoma; Renal carcinoma; Reporter; Reporting; Research; Resolution; Role; Route; Sarcomatoid Features; Sarcomatoid Renal Cell Carcinoma; Site; Suicide; System; Technology; Therapeutic; Therapeutic Intervention; Time; Tissues; Translational Research; United States National Institutes of Health; Work; addiction; base; cancer cell; cancer genomics; cancer therapy; clinical predictors; design; effective therapy; functional genomics; genome editing; genome-wide; host neoplasm interaction; human disease; improved; in vivo; innovation; neoplastic cell; new therapeutic target; novel; personalized approach; premalignant; pressure; programs; renal epithelium; repaired; response; screening; standard of care; targeted treatment; therapy resistant; tool; transcriptomics; transdifferentiation; tumor; tumor heterogeneity; tumor progression

Sarcomatoid renal cell carcinoma (sRCC) represents an aggressive group of renal epithelial tumors characterized by histopathological features of epithelial–mesenchymal plasticity (EMT) and prominent metastatic behavior. These malignancies are extremely challenging in the clinic, as they fail to respond to the standard-of- care therapeutic regimens for RCC. Furthermore, in spite of the remarkable advances in cancer genomics, there are still no reliable tools or biomarkers to predict the clinical course of the disease, particularly in the context of modern therapeutic interventions. Objectives. The long-term goal of this project is to identify the genomic and molecular drivers of malignant progression in sRCC, focusing on the role of EMT in clonal evolution, in the acquisition of metastatic potential and as a mechanism of adaptation to therapy. This will lead to the identification of context-specific vulnerabilities dictated by the specific genomic and molecular landscapes that characterize this aggressive subset of kidney cancer. Rationale and Hypothesis. Preliminary studies showing the emergence of specific patterns of chromosomal alterations led us to the hypothesis that the acquisition of chromosomal instability (CIN) during tumor evolution favors the selection of clones endowed with high cellular plasticity and prominent metastatic potential. Specific Aims. In the first aim we will provide a detailed spatial and temporal annotation of epithelial and mesenchymal population dynamics during malignant progression and in response to pharmacological interventions. The second aim will define the genomic and transcriptomic landscape of the malignant subpopulation and the interplay between these cellular compartments and the components of the TME. In the third aim we will identify context-specific vulnerabilities, defining the genetic dependencies of epithelial and mesenchymal cells. Significance. The approach will provide fundamental information about clonal dynamics, tumor–host interactions at a single-cell resolution, and tumor evolution in RCC, substantially improving our understanding of the genetic and molecular bases of the disease. Translational relevance. A detailed understanding of the genetic and molecular events driving malignant cell plasticity and the evolution to sRCC will provide the framework to predict the behavior of this heterogeneous group of tumors. Furthermore, the functional genomic approach will uncover context-specific vulnerabilities and provide novel drug targets in a disease class in urgent need of effective treatments. Innovation. The project is innovative from a conceptual and technological standpoint. Targeting cancer-specific weaknesses emerging in the context of cell plasticity, increased tumor heterogeneity, and clonal diversification is a promising approach tailored to the genetic and functional hallmarks of the disease. The technological tools and approaches are unique and highly innovative. The introduction of a lineage-tracing technology and an embedded dynamic reporter will allow us to address several open questions in the field of EMT going beyond the specific tumor type. The work will therefore provide the scientific community with a valuable tool for basic and translational research.

肉瘤样肾细胞癌（sRCC）是一组侵袭性肾上皮肿瘤 其特征在于上皮-间质可塑性（EMT）的组织病理学特征和显著的转移性 行为这些恶性肿瘤在临床上极具挑战性，因为它们不能对标准的 肾细胞癌的护理治疗方案。此外，尽管癌症基因组学取得了显著进展， 仍然没有可靠的工具或生物标志物来预测疾病的临床过程，特别是在 现代治疗干预。目标.该项目的长期目标是确定基因组和 sRCC恶性进展的分子驱动因素，关注EMT在克隆进化中的作用， 获得转移潜能并作为适应治疗的机制。这将导致识别 特定的基因组和分子格局决定了特定背景的脆弱性，这些特征 这种侵袭性肾癌基本原理和假设。初步研究显示， 染色体改变的特定模式的出现使我们假设， 肿瘤演变过程中的染色体不稳定性（CIN）有利于选择具有高细胞增殖能力的克隆。 可塑性和突出的转移潜力。具体目标。在第一个目标中，我们将提供详细的空间 以及恶性进展期间上皮和间充质群体动态的时间注释， 对药物干预的反应。第二个目标将定义基因组和转录组学 恶性亚群的景观以及这些细胞区室与肿瘤细胞之间的相互作用。 TME的组成部分。在第三个目标中，我们将确定特定环境的脆弱性， 上皮细胞和间充质细胞的依赖性。意义该方法将提供基本的 关于克隆动力学、单细胞分辨率下的肿瘤-宿主相互作用和肿瘤演变的信息， RCC，大大提高了我们对这种疾病的遗传和分子基础的理解。 翻译相关性。详细了解驱动恶性细胞的遗传和分子事件 塑性和演变为sRCC将提供框架，以预测这种非均质的行为 一组肿瘤。此外，功能基因组学方法将揭示特定环境的脆弱性， 在急需有效治疗的疾病类别中提供新的药物靶点。创新该项目 从概念和技术角度进行创新。针对癌症特有的弱点， 在细胞可塑性、肿瘤异质性增加和克隆多样化的背景下， 根据疾病的遗传和功能特征定制。技术工具和方法是 独特和高度创新。介绍了一种谱系追踪技术和一种嵌入式动态 报告者将使我们能够解决EMT领域的几个开放性问题，而不仅仅是特定的肿瘤类型。 因此，这项工作将为科学界提供基础研究和转化研究的宝贵工具。