Unraveling the regulatory circuits that drive Merkel cell carcinoma

解开驱动默克尔细胞癌的调节回路

• 批准号: 10462667
• 负责人: Megha Padi
• 金额: $ 34.26万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-10 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10462667
• 关键词: ATAC-seq; Actins; Affect; Arizona; Automobile Driving; BETA2 protein; Biological Assay; Biological Models; Biometry; Carcinogenesis Mechanism; Catalytic Domain; Cell Cycle; Cell Line; Cell model; Cells; Collaborations; Complement; Dana-Farber Cancer Institute; Data; Data Set; Effector Cell; Endocrine; Epithelial; Etiology; Event; Exhibits; Gene Expression; Genes; Genetic Transcription; Genomics; Goals; Heterogeneity; Human; Image; In Vitro; Infection; Large T Antigen; Lead; Lung; MYCL1 gene; Malignant Neoplasms; Measurement; Measures; Merkel Cells; Merkel cell carcinoma; Mesenchymal; Microtubules; Molecular; Mus; Mutation; Neoplasm Metastasis; Neuroendocrine Tumors; Neurosecretory Systems; Normal Cell; Oncogenes; Pancreas; Pathway interactions; Patients; Phenotype; Play; Polyomavirus; Process; Prostate; Protein Dynamics; Protein phosphatase; Proteins; RNA analysis; Role; Series; Signal Pathway; Signal Transduction; Skin; Skin Cancer; Small T Antigen; System; Testing; Therapeutic; Time; Tissues; Transforming Growth Factor beta; Tumor stage; Universities; Viral; Virus Diseases; Work; Xenograft Model; Xenograft procedure; base; cancer therapy; carcinogenesis; cell motility; cell type; chromatin remodeling; genome-wide; knock-down; migration; network models; neuroendocrine cancer; neurogenesis; novel therapeutics; programs; relating to nervous system; response; targeted treatment; transcription factor; transcriptome sequencing; tumor

Neuroendocrine tumors arise in multiple tissues, including the skin, lung, prostate, and pancreas, and share common neural and endocrine phenotypes. Discovering their mechanism of carcinogenesis is challenging due to our inability to directly observe tumor formation, as well as the mutational heterogeneity of established tumors. Unlike tumors that arise through random mutational processes, Merkel cell carcinoma (MCC) is a neuroendocrine skin cancer that can be caused by infection with Merkel cell polyomavirus (MCPyV) and whose mechanisms can be studied in vitro. MCPyV contains two oncogenes, the small T (ST) and large T (LT) antigens. The impact of ST on cell migration and LT on the cell cycle are known, but there is no genome-wide, quantitative understanding of how ST and LT reprogram normal cells into a neuroendocrine tumor prone to metastasis. Our preliminary RNA-sequencing data from normal cells expressing MCPyV oncogenes indicates that LT transcriptionally alters invasion and migration-related pathways such as WNT and TGF-beta signaling, in a manner that is similar to expression changes in human MCC tumors and metastases. Using this system, we can also measure gene expression dynamics and directly observe the temporal sequence of molecular events underlying carcinogenesis in a way that cannot be achieved through static tumor measurements alone. The viral etiology of MCC therefore provides us with a unique opportunity to systematically investigate and quantify the regulatory circuits driving neuroendocrine tumor formation and metastasis. In Aim 1, we will reconstruct the host transcriptional networks and signaling pathways utilized by MCPyV to promote cell motility and invasion, determine the roles of LT, WNT, and TGF-beta in promoting metastasis, and predict the optimal strategy for inhibiting these mechanisms. In collaboration with metastasis experts at the University of Arizona, we will test our predictions in a series of MCC model systems, including cell-based migration and invasion assays and mouse xenograft studies. In Aim 2, we will measure protein dynamics of neural regulators activated by ST and LT and integrate them with gene expression and ATAC-seq data to build a network model of the cell fate transition induced by MCPyV. Our work will provide a systems-level analysis of regulatory circuits underlying metastasis and cellular reprograming in neuroendocrine tumors, and will identify new therapies for Merkel cell carcinoma that may be applicable to other tumor types.

神经内分泌肿瘤在多种组织中出现，包括皮肤，肺，前列腺和胰腺，并共享 常见的神经和内分泌表型。发现他们的癌变机制是具有挑战性的 为了我们无法直接观察到肿瘤的形成以及已建立肿瘤的突变异质性。 与通过随机突变过程产生的肿瘤不同，默克尔细胞癌（MCC）是 神经内分泌皮肤癌可能是由默克尔细胞多瘤病毒（MCPYV）引起的，并且 可以在体外研究机制。 MCPYV包含两个癌基因，小t（st）和大t（lt）抗原。 已知ST对细胞迁移和LT对细胞周期的影响是已知的，但是没有基因组的定量 了解ST和LT重编程正常细胞如何进入神经内分泌肿瘤容易转移。我们的 来自表达MCPYV Oncogenes的正常细胞的初步RNA测序数据表明LT 转录在A中改变了入侵和迁移相关的途径，例如Wnt和TGF-BETA信号， 类似于人类MCC肿瘤和转移中的表达变化的方式。使用此系统，我们可以 还测量基因表达动力学并直接观察分子事件的时间序列 潜在的致癌作用是无法通过仅通过静态肿瘤测量来实现的方式。病毒 因此，MCC的病因为我们提供了系统调查和量化的独特机会 驱动神经内分泌肿瘤形成和转移的调节回路。在AIM 1中，我们将重建主机 MCPYV使用的转录网络和信号通路来促进细胞运动和侵袭， 确定LT，Wnt和TGF-beta在促进转移中的作用，并预测最佳策略 抑制这些机制。与亚利桑那大学的转移专家合作，我们将测试 我们在一系列MCC模型系统中的预测，包括基于细胞的迁移和入侵分析和 小鼠异种移植研究。在AIM 2中，我们将测量由ST和ST激活的神经调节剂的蛋白质动力学 LT并将它们与基因表达和ATAC-SEQ数据集成在一起，以构建细胞命运的网络模型 MCPYV诱导的过渡。我们的工作将提供对监管电路的系统级分析 神经内分泌肿瘤中的转移和细胞重编程，并将确定默克尔细胞的新疗法 可能适用于其他肿瘤类型的癌。