Androgen receptor function in melanoma

雄激素受体在黑色素瘤中的功能

• 批准号: 10709864
• 负责人: GIAN-PAOLO DOTTO
• 金额: $ 44.8万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-23 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10709864
• 关键词: AR gene; Address; Age; Androgen Receptor; Androgen Suppression; Androgens; BRAF gene; Biochemical; Cell Aging; Cells; Collection; Cytoplasm; Cytotoxic T-Lymphocytes; DNA; DNA Damage; DNA Repair; Data; Development; Epigenetic Process; Estrogens; Extravasation; Female; Gene Expression Profile; Gene Silencing; Genes; Genetic; Genetic Transcription; Genome Stability; Gonadal Steroid Hormones; Immunocompetent; Incidence; Infiltration; Inflammatory; Lamin Type A; Lamins; Ligands; Link; Macrophage; Maintenance; Malignant Neoplasms; Melanoma Cell; Modeling; Mutation; Nuclear Envelope; Nuclear Lamin; Nuclear Receptor Coactivator 4; Organ; Pathway interactions; Patients; Phosphorylation; Play; Population; Predisposition; Process; Proliferating; Protein phosphatase; Proteins; RNA Helicase; Receptor Inhibition; Receptor Signaling; Resistance; Resources; Role; Sex Differences; Signal Transduction; T-Cell Activation; Testing; Up-Regulation; Validation; Work; cancer type; clinically significant; ds-DNA; genome integrity; hormonal signals; in vivo; inhibitor; male; melanoma; mouse model; overexpression; patient derived xenograft model; patient response; pharmacologic; prevent; prognostic significance; receptor expression; receptor function; response; self-renewal; sex; sexual dimorphism; transcriptomics; treatment response; tumor; tumorigenesis

Abstract Malignant melanoma is an example of primary clinical significance for investigating sex-related differences in cancer arising in organs with non-reproductive functions. Differences in sex hormone levels and in downstream pathways are likely to play a key role, which is however still poorly understood. Our main working hypothesis is that androgen receptor (AR) and associated proteins converge on control of melanoma development and response to treatment. In recent work, we have found that genetic and pharmacological suppression of AR activity in a large panel of melanoma cells reduces self-renewal potential and tumorigenesis, inducing double strand DNA damage and cytoplasmic leakage, a STING-dependent pro-inflammatory cascade and a gene expression signature associated with better patients' survival. Based on further preliminary data, we will test two specific hypotheses: 1) AR signaling plays a key role in melanoma cells at the intersection between gene transcription and DNA repair / genomic stability with nuclear lamins as co-determinants. We will probe into the biochemical and functional significance of endogenous AR-lamin interactions and AR-dependent lamin A/C association with the PPP1 protein phosphatase, impinging on lamin phosphorylation at critical residues, and with the DDX3X and DDX3Y RNA helicases, encoded by X- and Y-linked genes and with expression of prognostic significance for female and male patients, respectively. 2) Targeting AR is of translational significance for preventing / counteracting resistance of melanomas with BRAFv600 mutations to BRAF inhibitors (BRAFi). In preliminary work, we found striking up-regulation of AR expression in response to BRAFi, proliferation and tumorigenesis of BRAFi resistant melanoma cells are suppressed by AR inhibition, AR overexpression is by itself sufficient to confer BRAFi resistance. In further studies we will assess to what extent suppression of AR expression and activity has an impact on melanoma cell subpopulations with intrinsic BRAFi resistance and/or BRAFi-induced epigenetic reprogramming. We will analyze a collection of freshly derived cells from Patient- Derived Xenografts (PDX) of BRAFi sensitive and resistant melanomas and assess to what extent the beneficial effects of suppression of AR signalling occur in vivo, restoring one or more aspects of the BRAFi response of the corresponding PDXs.

抽象的 恶性黑色素瘤是研究性别相关性具有主要临床意义的一个例子 具有非生殖功能的器官中发生的癌症的差异。性别差异 激素水平和下游途径可能发挥关键作用，但这仍然是 不太了解。我们的主要工作假设是雄激素受体（AR）和相关的 蛋白质集中控制黑色素瘤的发展和对治疗的反应。近来 工作中，我们发现在一大组中 AR 活性的遗传和药理学抑制 黑色素瘤细胞降低自我更新潜力和肿瘤发生，诱导双链 DNA 损伤和细胞质渗漏、STING 依赖性促炎级联和基因 表达特征与更好的患者生存相关。根据进一步的初步数据， 我们将测试两个具体假设：1) AR 信号在黑色素瘤细胞中发挥关键作用 基因转录和 DNA 修复/基因组稳定性与核纤层蛋白之间的交叉 共同决定因素。我们将探讨内源性的生化和功能意义 AR-核纤层蛋白相互作用以及 AR 依赖性核纤层蛋白 A/C 与 PPP1 蛋白的关联 磷酸酶，影响关键残基的核纤层蛋白磷酸化，并使用 DDX3X 和 DDX3Y RNA 解旋酶，由 X 和 Y 连锁基因编码，并表达预后 分别对女性和男性患者具有重要意义。 2) AR的目标是平移的 对于预防/抵抗带有 BRAFv600 突变的黑色素瘤的耐药性具有重要意义 BRAF抑制剂（BRAFi）。在前期工作中，我们发现 AR 表达显着上调 对 BRAFi 的反应、BRAFi 抗性黑色素瘤细胞的增殖和肿瘤发生 由于 AR 抑制作用被抑制，AR 过度表达本身足以赋予 BRAFi 抗性。 在进一步的研究中，我们将评估 AR 表达和活性的抑制在多大程度上具有 对具有内在 BRAFi 抗性和/或 BRAFi 诱导的黑色素瘤细胞亚群的影响 表观遗传重编程。我们将分析来自患者的新鲜细胞集合 - BRAFi 敏感和耐药黑色素瘤的衍生异种移植物 (PDX) 并评估其程度 抑制 AR 信号传导的有益作用在体内发生，恢复一个或多个方面 相应 PDX 的 BRAFi 响应。