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

肉瘤样肾细胞癌(SRCC)是一组侵袭性肾上皮肿瘤。 以上皮-间充质可塑性(EMT)和显著转移为特征的组织病理学特征 行为。这些恶性肿瘤在临床上极具挑战性，因为它们无法对- 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的进展，但 仍然没有可靠的工具或生物标志物来预测疾病的临床进程，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，重点是EMT在克隆进化中的作用，在 获得转移潜能，并作为适应治疗的机制。这将导致身份识别 由特定的基因组和分子环境决定的特定于上下文的漏洞 这是肾癌的侵袭性亚群。理论基础和假设。初步研究显示 特定的染色体改变模式的出现使我们产生了一种假设，即 肿瘤进化过程中的染色体不稳定性(CIN)有利于选择具有高细胞性的克隆 可塑性和显著的转移潜能。明确的目标。在第一个目标中，我们将提供详细的空间 恶性进展和癌变过程中上皮和间充质种群动态的时间注释 对药物干预的反应。第二个目标将定义基因组和转录组 恶性亚群的景观以及这些细胞隔间和 TME的组件。在第三个目标中，我们将识别特定于环境的漏洞，定义基因 上皮细胞和间充质细胞的依赖性。意义重大。该方法将提供基本的 在单细胞分辨率下的克隆动力学、肿瘤-宿主相互作用和肿瘤进化的信息 RCC，大大提高了我们对这种疾病的遗传和分子基础的了解。 翻译关联性。详细了解驱动恶性细胞的遗传和分子事件 可塑性和向SRCC的演化将为预测这种非均质的行为提供框架 一组肿瘤。此外，功能基因组方法将发现特定于上下文的漏洞和 在急需有效治疗的疾病类别中提供新的药物靶点。创新。该项目是 从概念和技术的角度进行创新。针对癌症特有的弱点，在 在细胞可塑性、肿瘤异质性增加和克隆多样化的背景下，这是一个有希望的方法。 根据疾病的遗传和功能特征量身定做。技术工具和方法是 独树一帜，极具创新性。介绍一种血统追踪技术和一种嵌入式动态 记者将允许我们回答EMT领域的几个悬而未决的问题，这些问题超出了特定的肿瘤类型。 因此，这项工作将为科学界提供基础研究和翻译研究的宝贵工具。

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.