Role of Notch Signaling in Melanoma Transdifferentiation and Tumor Progression

Notch 信号传导在黑色素瘤转分化和肿瘤进展中的作用

基本信息

项目摘要

DESCRIPTION (provided by applicant): Cutaneous melanoma, the deadliest form of skin cancer, arises from neural crest derived melanocytes. Much progress has been made in delineating molecular events that initiate the cascade of malignant changes leading to metastatic melanoma. These advances have led to some remarkable improvements in treatment of melanoma. However, the notorious intrinsic resistance to conventional therapies and development of treatment resistance to targeted therapies continue to be vexing problems highlighting the need to explore additional avenues for preventing melanoma development and progression. In this context, the role for Notch signaling in melanoma remains to be fully understood and exploited. Notch signaling, an important cell signaling mechanism, is known to play a role in melanocyte development. However, molecular mechanisms and the specific roles Notch plays in melanoma development and progression are not completely understood. Preliminary data obtained in my laboratory showed a possible biphasic role for Notch signaling in melanoma tumor progression. In skin resident benign neo-plastic melanocytes and early primary melanoma, a downregulation of Notch signaling and its effector HES1, a transcriptional repressor, allows elaboration of neuronal differentiation. This is indicated by the expression of a protein, MAP2 that is normally present only in terminally differentiated neurons that lack ability to divide. A retrospective survival analysis showed that patients whose primary skin tumors were MAP2-positive survived significantly longer without melanoma recurrence than those diagnosed with MAP2-negative melanoma. MAP2 is absent or found less frequently in metastatic melanoma. In agreement with its primary function of binding to and stabilizing microtubules, MAP2 alters the dynamic instability of microtubules and induces mitotic spindle defects in melanoma. Preliminary data also showed that molecular players that initiate the malignant changes in melanocytes also play a role in activation of this neuronal differentiation marker. Thus, activation of a neuron-specific gene in melanocytes at early stages of malignant transformation correlates with inhibition of proliferation in vitro and tumor growth and progression in vivo. Based on these data, we hypothesized that Notch signaling, has a dual or biphasic role in melanoma. First, Notch signaling is downregulated during early steps in malignant transformation by sustained oncogenic signaling to promote neuronal differentiation as a fail-safe mechanism against melanoma tumorigenesis, and additional genetic events such as loss of PTEN then lead to upregulation of Notch signaling to support melanoma tumor progression. To test this hypothesis, we will use a combination of in vitro and in vivo approaches to accomplish the following Aims: In Aim 1, we will study mechanisms of transdifferentiation in melanocytes and patient-derived melanoma using primary melanocytes and a panel of well-characterized melanoma cell lines, we will investigate the molecular mechanisms. In Aim 2, we will investigate the role of Notch signaling and neuronal differentiation in melanomagenesis using metastatic melanoma cells with stable knockdown of HES1and/or treated with inhibitors of Notch signaling in immunocompromised mice, and a genetic cross between transgenic mice with inducible MPA2 expression in melanocytes and BrafCa/Pten-/- mice. In Aim 3, we will evaluate the prognostic significance of Notch in melanoma employing quantitative immunohistochemical method to analyze an in- house created melanoma tissue microarray consisting of 225 stage I-III primary melanoma specimens with complete clinical history. The hypothesis on the dual role of Notch in transdifferentiation and use of combination of mouse genetic model and a fully annotated melanoma tissue microarray are the innovative aspects of the proposed research. Data obtained from these studies have the potential to uncover more reliable prognostic markers for melanoma aggressiveness and impact the management of aggressive cutaneous melanoma.
描述(由申请人提供): 皮肤黑色素瘤是最致命的皮肤癌,由神经嵴衍生的黑色素细胞产生。在描述引发恶性变化并导致转移性黑色素瘤的级联反应的分子事件方面已经取得了很大进展。这些进步使黑色素瘤的治疗取得了一些显着的进步。然而,对传统疗法的臭名昭著的内在耐药性和对靶向疗法的治疗耐药性的发展仍然是令人烦恼的问题,突出表明需要探索其他途径来预防黑色素瘤的发生和进展。在这种情况下,Notch 信号传导在黑色素瘤中的作用仍有待充分理解和利用。 Notch 信号传导是一种重要的细胞信号传导机制,已知在黑素细胞发育中发挥作用。然而,Notch 在黑色素瘤发生和进展中的分子机制和具体作用尚不完全清楚。 我的实验室获得的初步数据表明,Notch 信号传导在黑色素瘤进展中可能具有双相作用。在皮肤良性肿瘤性黑色素细胞和早期原发性黑色素瘤中,Notch 信号传导及其效应子 HES1(一种转录抑制因子)的下调可以促进神经元分化。这是 MAP2 蛋白的表达表明该蛋白通常仅存在于缺乏分裂能力的终末分化神经元中。一项回顾性生存分析显示,原发性皮肤肿瘤为 MAP2 阳性的患者在没有黑色素瘤复发的情况下的生存时间明显长于诊断为 MAP2 阴性黑色素瘤的患者。 MAP2 在转移性黑色素瘤中不存在或较少发现。与其结合和稳定微管的主要功能一致,MAP2 改变微管的动态不稳定性并诱导黑色素瘤中的有丝分裂纺锤体缺陷。初步数据还表明,引发黑素细胞恶性变化的分子参与者也在这种神经元分化标记物的激活中发挥作用。因此,恶性转化早期黑素细胞中神经元特异性基因的激活与体外增殖抑制和体内肿瘤生长和进展相关。基于这些数据,我们假设 Notch 信号在黑色素瘤中具有双重或双相作用。首先,Notch 信号在恶性转化的早期步骤中通过持续的致癌信号下调,以促进神经元分化,作为对抗黑色素瘤肿瘤发生的自动防故障机制,而 PTEN 丢失等其他遗传事件则导致 Notch 信号上调,以支持黑色素瘤肿瘤进展。为了检验这一假设,我们将结合使用体外和体内方法来实现以下目标:在目标 1 中,我们将使用原代黑素细胞和一组充分表征的黑素细胞来研究黑素细胞和患者来源的黑色素瘤的转分化机制。黑色素瘤细胞系,我们将研究其分子机制。在目标 2 中,我们将使用稳定敲低 HES1 和/或用 Notch 信号抑制剂治疗的免疫功能低下小鼠的转移性黑色素瘤细胞,以及具有可诱导 MPA2 表达的转基因小鼠之间的遗传杂交来研究 Notch 信号传导和神经元分化在黑色素瘤生成中的作用。黑素细胞和 BrafCa/Pten-/- 小鼠。在目标 3 中,我们将采用定量免疫组织化学方法分析内部创建的黑色素瘤组织微阵列,评估 Notch 在黑色素瘤中的预后意义,该微阵列由 225 个具有完整临床病史的 I-III 期原发性黑色素瘤标本组成。 Notch在转分化中的双重作用的假设以及小鼠遗传模型和完全注释的黑色素瘤组织微阵列的结合使用是本研究的创新点。从这些研究中获得的数据有可能发现更可靠的黑色素瘤侵袭性预后标志物,并影响侵袭性皮肤黑色素瘤的治疗。

项目成果

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Vijayasaradhi Setaluri其他文献

Vijayasaradhi Setaluri的其他文献

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{{ truncateString('Vijayasaradhi Setaluri', 18)}}的其他基金

BLRD Research Career Scientist Award Application
BLRD 研究职业科学家奖申请
  • 批准号:
    10702086
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
Role of EPAC Signaling in Melanoma Progression
EPAC 信号传导在黑色素瘤进展中的作用
  • 批准号:
    9892600
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Role of EPAC Signaling in Melanoma Progression
EPAC 信号传导在黑色素瘤进展中的作用
  • 批准号:
    10292971
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Role of EPAC Signaling in Melanoma Progression
EPAC 信号传导在黑色素瘤进展中的作用
  • 批准号:
    10515639
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Role of EPAC Signaling in Melanoma Progression
EPAC 信号传导在黑色素瘤进展中的作用
  • 批准号:
    10057218
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Role of Notch Signaling in Melanoma Transdifferentiation and Tumor Progression
Notch 信号传导在黑色素瘤转分化和肿瘤进展中的作用
  • 批准号:
    9794743
  • 财政年份:
    2014
  • 资助金额:
    --
  • 项目类别:
18th Annual Meeting of the PanAmerican Society of Pigment Cell Research
第十八届泛美色素细胞研究学会年会
  • 批准号:
    8597622
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:
Role of TRPM1 (Melastatin1) in the Biology of Human Melanocytes
TRPM1(Melastatin1)在人类黑素细胞生物学中的作用
  • 批准号:
    7450396
  • 财政年份:
    2008
  • 资助金额:
    --
  • 项目类别:
Prognostic Significance of Neuronal Differentiation of Cutaneous Melanoma
皮肤黑色素瘤神经元分化的预后意义
  • 批准号:
    7587326
  • 财政年份:
    2008
  • 资助金额:
    --
  • 项目类别:
Role of TRPM1 (Melastatin1) in the Biology of Human Melanocytes
TRPM1(Melastatin1)在人类黑素细胞生物学中的作用
  • 批准号:
    7769851
  • 财政年份:
    2008
  • 资助金额:
    --
  • 项目类别:

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