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

• 批准号: 10659255
• 负责人: Eva Hernando
• 金额: $ 50.44万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 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/10659255
• 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; Endowment; Epidermis; Epigenetic Process; Excision; Genes; Genetic Transcription; Growth; Heterogeneity; Human; Hypermethylation; Immunohistochemistry; In Situ Hybridization; In Vitro; Intervention; Invaded; Malignant Neoplasms; Measures; Melanoma Cell; Metastatic Melanoma; Metastatic/Recurrent; Methylation; Modeling; Molecular; Morbidity - disease rate; Mus; Neoplasm Metastasis; Neural Crest; Neural Crest Cell; Newly Diagnosed; Nuclear Receptors; Organ; Outcome; Patient Selection; Patient-Focused Outcomes; Patients; Phenotype; Prognosis; Prognostic Marker; Prospective cohort; Protein Isoforms; Recurrence; Regulation; Resected; Risk; Role; Sampling; Site; Skin; Testing; Transcription Initiation Site; Treatment outcome; Tumor stage; Work; Xenograft procedure; apoAI regulatory protein-1; biomarker panel; cancer cell; clinical decision-making; cofactor; cost; demethylation; derepression; epithelial to mesenchymal transition; gain of function; 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

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，但它们的失调允许 癌细胞去分化成转录异质性细胞状态。这种转录异质性 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。 转移性扩散尽管这种可塑性通常与癌症进展和预后不良相关， 对于患者，尚不清楚表观遗传变化如何侵蚀发育限制，使细胞获得 它们在转录上不同的细胞状态之间相互转换时的生物学特征谱。 通过分析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NR 2F 2的另一种启动子在20例患者中发生去甲基化， 转移性黑素瘤这种表观遗传变化允许NR 2F 2-亚型2 -在神经嵴细胞中表达， 当它们分化成黑素细胞时沉默-重新表达。初步功能研究 提示NR 2F 2-同种型2表达对于转移而不是原发性黑素瘤生长是关键， 神经嵴和上皮-间充质转化相关基因集。根据这些研究，我们 假设NR 2F 2-亚型2的去抑制会引发影响转录的变化 定义黑色素瘤细胞的表型异质性，允许这些细胞的一个子集扩散 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素瘤模型中抑制或促进NR 2F 2-同种型2启动子甲基化 测量黑色素瘤异质性和转移潜力的变化; ·鉴定受NR 2F 2-同种型2及其配偶体影响的转录网络;以及 ·将原发性患者中NR 2F 2-同种型2、其转录辅因子和靶标的表达相关联 原发性黑色素瘤切除术后转移性复发的样本。 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 因为它将： ·提供一个概念性框架，说明替代转录因子亚型的表观遗传失调 影响黑色素瘤细胞去分化为表型异质的细胞状态; ·鉴定导致早期肿瘤转移进展的细胞状态;和 ·识别预后标志物和治疗靶点。 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，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于毒副作用 不必要的干预的影响和成本。