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的主要临床意义的一个例子。 癌症发生在具有非生殖功能的器官上的差异。性别差异 荷尔蒙水平和下游途径可能发挥关键作用，但这仍然是 人们对此知之甚少。我们的主要工作假设是雄激素受体(AR)和相关的 蛋白质集中在控制黑色素瘤的发展和对治疗的反应上。在最近 工作中，我们发现，遗传和药物对AR活性的抑制在一个大小组中 黑色素瘤细胞减少自我更新能力和肿瘤发生，诱导双链DNA 损伤和细胞质渗漏，依赖刺痛的促炎级联反应和一个基因 表情特征与患者更好的生存相关。根据进一步的初步数据， 我们将检验两个具体的假设：1)AR信号在黑色素瘤细胞中发挥关键作用 核蛋白与基因转录和DNA修复/基因组稳定性的交集 共同决定因素。我们将探讨内源激素的生化和功能意义。 AR-lamin相互作用及依赖AR的lamin A/C与PPP1蛋白的关系 磷酸酶，影响关键残基的层蛋白磷酸化，并与DDX3X和 DDX3Y RNA解旋酶，由X和Y连锁基因编码，具有预后意义 对女性患者和男性患者分别具有重要意义。2)定位AR具有平移性 BRAFV600基因突变对黑色素瘤耐药的预防和逆转意义 BRAF抑制剂(BRAFi)。在前期工作中，我们发现AR表达上调。 耐BRAFi黑色素瘤细胞对BRAFi的反应、增殖和致瘤性 受AR抑制的抑制，AR的过度表达本身就足以赋予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 BRAFi固有抵抗和/或BRAFi诱导对黑色素瘤细胞亚群的影响 表观遗传重新编程。我们将分析从患者身上收集的新鲜细胞- 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信号的有益效果在体内发生，恢复一个或多个方面 相应PDX的BRAFi响应。