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，但它们的放松管制允许 癌细胞将分化为转录的异质细胞态。这种转录异质性 表型可塑性定义了许多癌症，包括黑色素瘤，被认为是 转移性扩散。尽管这种可塑性通常与癌症的进展和预后不良相关 患者，尚不清楚表观遗传变化如何侵蚀发育的限制，以使细胞获取 生物学特征频谱在转录具有独特的细胞状态之间相互互换。 通过分析人类原代和转移性皮肤黑色素瘤的DNA甲基化谱 患者我们发现核接收器NR2F2的替代启动子在 转移性黑色素瘤。这种表观遗传学变化允许NR2F2-异型2 - 在神经rest细胞和 当它们分化为黑素细胞时被沉默 - 重新表达。初步功能研究 建议NR2F2-异型2表达对转移至关重要，但不是原发性黑色素瘤的生长，它影响 神经rest和上皮到间质转变相关的基因集。基于这些研究，我们 假设NR2F2-异型的抑制2引起了影响的转录变化 定义黑色素瘤细胞的表型异质性，使这些细胞的一部分传播 并转移到遥远的器官。为了检验这一假设，我们建议： •在小鼠和患者衍生的黑色素瘤模型中抑制或促进NR2F2-异型2启动子甲基化 衡量黑色素瘤异质性和转移性潜力的变化； •确定受NR2F2-异型2及其合作伙伴影响的转录网络；和 •将NR2F2-异型2的表达（其转录副因素和靶标在原发性患者中 原发性黑色素瘤切除术后具有转移性复发的样品。 成功完成该项目有望显着影响黑色素瘤和转移场 因为它会： •提供一个概念框架，说明如何表观对替代转录因子同工型的表观遗传降低调节 影响黑色素瘤细胞对表型异质细胞态的脱不同。 •确定导致早期肿瘤转移进展的细胞状态；和 •确定预后标记和治疗靶标。 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性进展，从而减少 复发性黑色素瘤患者的发病率和死亡率，同时保留毒性一面的无肿瘤患者 不必要的干预措施的影响和成本。