Defining epigenetic regulators of tumor heterogeneity and metastasis in melanoma

定义黑色素瘤肿瘤异质性和转移的表观遗传调节因子

基本信息

批准号：
10512423
负责人：
Eva Hernando
金额：
$ 50.76万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-05 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10512423
关键词：
Adjuvant Therapy Affect Biological Body part Candidate Disease Gene Cell Differentiation process Cells Cessation of life CpG dinucleotide Cutaneous Melanoma DNA Binding Domain DNA Methylation DNA analysis Data Dermis Development Diagnosis Dimerization Disease Distant Epidermis Epigenetic Process Excision Genes Genetic Transcription Growth Heterogeneity Human Hypermethylation Immunohistochemistry In Situ Hybridization In Vitro Intervention Invaded Light Malignant Neoplasms Measures Melanoma Cell Metastatic Melanoma Methylation Modeling Molecular Morbidity - disease rate Mus Neoplasm Metastasis Neural Crest Neural Crest Cell Newly Diagnosed Nuclear Receptors Organ Outcome Patient-Focused Outcomes Patients Phenotype Plant Roots Prognosis Prognostic Marker Prospective cohort Protein Isoforms Recurrence Regulation Repression Resected Risk Role Sampling Site Skin Testing Transcription Initiation Site Treatment outcome Tumor stage Work Xenograft procedure apoAI regulatory protein-1 base biomarker panel cancer cell clinical decision-making cost demethylation epithelial to mesenchymal transition genetic signature human model improved in vivo Model insight loss of function melanocyte melanoma molecular marker mortality mouse model novel patient derived xenograft model prevent primary outcome promoter screening side effect single molecule therapeutic target transcription factor tumor tumor heterogeneity tumor progression

项目摘要

Epigenetic landscapes restrict the developmental potential of differentiated cells, but their deregulation allows cancer cells to de-differentiate into transcriptionally heterogeneous cell states. This transcriptional heterogeneity and phenotypic plasticity define many cancers, including melanoma, and are thought to be the root cause of metastatic spread. Although this plasticity often correlates with cancer progression and poor prognosis in patients, it is still unclear how epigenetic changes erode developmental constraints to allow cells to acquire a spectrum of biological features as they interconvert between transcriptionally distinctive cell states. By analyzing the DNA methylation profiles of primary and metastatic cutaneous melanomas from human patients we discovered an alternative promoter of the nuclear receptor NR2F2 becomes de-methylated in metastatic melanomas. This epigenetic change allows NR2F2-isoform 2 – expressed in neural crest cells and silenced when they differentiate into melanocytes – to become re-expressed. Preliminary functional studies suggest NR2F2-isoform 2 expression is critical for metastasis but not primary melanoma growth and it affects neural crest and epithelial-to-mesenchymal transition associated gene sets. Based on these studies, we hypothesize that de-repression of NR2F2-isoform 2 elicits transcriptional changes that influence the phenotypic heterogeneity that defines melanoma cells, allowing a subset of these cells to disseminate and metastasize to distant organs. To test this hypothesis, we propose to: • inhibit or promote NR2F2-isoform 2 promoter methylation in mouse and patient-derived melanoma models to measure changes in melanoma heterogeneity and metastatic potential; • identify transcriptional networks that are influenced by NR2F2-isoform 2 and its partners; and • correlate the expression of NR2F2-isoform 2, its transcriptional co-factors and targets in primary patient samples with their metastatic recurrence after primary melanoma resection. Successful completion of this project promises to significantly impact both the melanoma and metastasis fields because it will: • provide a conceptual framework for how epigenetic de-regulation of an alternative transcription factor isoform influences the de-differentiation of melanoma cells into phenotypically heterogeneous cell states; • identify the cell state responsible for metastatic progression in early-stage tumors; and • identify prognostic markers and therapeutic targets. These will allow us to predict, prevent, or treat metastatic progression in early-stage melanoma patients, reducing morbidity and mortality in patients with recurrent melanoma, while sparing tumor-free patients from toxic side effects and cost of unnecessary interventions.

表观遗传景观限制了分化细胞的发育潜力，但它们的放松管制允许癌细胞去分化为转录异质性细胞状态。和表型可塑性定义了许多癌症，包括黑色素瘤，并被认为是癌症的根本原因尽管这种可塑性通常与癌症进展和不良预后相关。对于患者来说，目前尚不清楚表观遗传变化如何消除发育限制，从而使细胞获得生物特征谱在转录上独特的细胞状态之间相互转换。通过分析人类原发性和转移性皮肤黑色素瘤的 DNA 甲基化谱我们发现核受体 NR2F2 的替代启动子在患者中去甲基化这种表观遗传变化允许 NR2F2-亚型 2 在神经嵴细胞中表达当它们分化为黑素细胞时被沉默——重新表达的初步功能。表明 NR2F2-isoform 2 表达对于转移至关重要，但对原发性黑色素瘤生长并不重要，并且它会影响基于这些研究，我们研究了神经嵴和上皮间质转化相关的基因集。 NR2F2-isoform 2 的去抑制会引发转录变化，从而影响黑色素瘤细胞的表型异质性，允许这些细胞的子集传播并转移到远处器官为了检验这一假设，我们建议： • 在小鼠和患者来源的黑色素瘤模型中抑制或促进 NR2F2-isoform 2 启动子甲基化测量黑色素瘤异质性和转移潜力的变化； • 确定受NR2F2-isoform 2 及其伙伴影响的转录网络；以及 • 将原发患者中NR2F2-亚型2、其转录辅助因子和靶标的表达关联起来原发性黑色素瘤切除后出现转移复发的样本。该项目的成功完成有望对黑色素瘤和转移领域产生重大影响因为它会： • 为替代转录因子亚型的表观遗传失调提供概念框架影响黑色素瘤细胞去分化为表型异质细胞状态； • 确定导致早期肿瘤转移进展的细胞状态；以及 • 确定预后标志物和治疗目标。这些将使我们能够预测、预防或治疗早期黑色素瘤患者的转移进展，从而减少复发性黑色素瘤患者的发病率和死亡率，同时使无肿瘤患者免受毒副作用的影响不必要干预的影响和成本。