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.

摘要 恶性黑色素瘤是研究性相关性的主要临床意义的例子。 在非生殖功能器官中产生的癌症的差异。性别差异 激素水平和下游途径可能发挥关键作用，然而， 不太了解。我们的主要工作假设是雄激素受体（AR）和相关的 蛋白质集中于控制黑色素瘤的发展和对治疗的反应。近几 工作中，我们已经发现，在一个大的面板AR活性的遗传和药理学抑制， 降低了黑色素瘤细胞的自我更新能力和肿瘤发生，诱导双链DNA 损伤和细胞质渗漏，STING依赖性促炎级联反应和基因 与更好的患者存活率相关的表达特征。根据进一步的初步数据， 我们将检验两个特定的假设：1）AR信号在黑色素瘤细胞中起关键作用， 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物化学和功能意义， AR-核纤层蛋白相互作用和AR依赖性核纤层蛋白A/C与PPP 1蛋白的关联 磷酸酶，冲击核纤层蛋白磷酸化的关键残基，并与DDX 3X和 DDX 3 Y RNA解旋酶，由X-和Y-连锁基因编码，表达预后性 分别对女性和男性患者具有显著性。2)靶向AR是翻译的 预防/抵消BRAFv 600突变黑色素瘤对 BRAF抑制剂（BRAFi）。在前期工作中，我们发现在正常小鼠中AR表达显著上调。 BRAFi抗性黑色素瘤细胞对BRAFi的应答、增殖和肿瘤发生是 通过抑制AR，AR过表达本身足以赋予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影响了 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一组来自患者的新鲜细胞- BRAFi敏感性和抗性黑色素瘤的衍生异种移植物（PDX），并评估在何种程度上 抑制AR信号传导的有益作用在体内发生， 对应的PDX的BRAFi响应。