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: 9275430
• 负责人: Vijayasaradhi Setaluri
• 金额: --
• 依托单位: WM S. MIDDLETON MEMORIAL VETERANS HOSP
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-10-01 至 2018-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9275430
• 关键词: Advanced Malignant Neoplasm; Agreement; Attenuated; BRAF gene; Benign; Binding; Biology; Cell Cycle Arrest; Cell Line; Cells; Clinical; Combination Drug Therapy; Cutaneous Melanoma; Data; Defect; Development; Developmental Process; Diagnosis; Differentiation Antigens; Disease; Disease-Free Survival; Down-Regulation; ES01; Early Diagnosis; Event; Exhibits; Exposure to; Genes; Genetic; Genetic Crosses; Genetic Models; Growth; Immunocompromised Host; In Vitro; Laboratories; Lead; Malignant - descriptor; Malignant Neoplasms; Melanins; Melanocytic nevus; Melanoma Cell; Metastatic Melanoma; Metastatic to; Methods; Methylation; Microtubule Stabilization; Microtubule-Associated Protein 2; Microtubules; Military Personnel; Mitotic; Mitotic spindle; Molecular; Mus; Neoplasm Metastasis; Neural Crest; Neuronal Differentiation; Neurons; Oncogenic; PTEN gene; Patients; Pigments; Play; Premalignant; Prevention; Primary Lesion; Prognostic Marker; Proteins; Publishing; Recording of previous events; Recurrence; Regulation; Research; Resistance; Resistance development; Risk; Role; Sea; Signal Pathway; Signal Transduction; Skin; Skin Cancer; Skin Neoplasms; Specimen; Survival Analysis; Tamoxifen; Testing; The Sun; Tissue Microarray; Transcription Repressor/Corepressor; Transgenic Mice; Ultraviolet Rays; United States; Up-Regulation; Veterans; advanced disease; attenuation; base; brain cell; cancer diagnosis; conventional therapy; demethylation; effective therapy; in vivo; inducible gene expression; inhibitor/antagonist; innovation; knock-down; melanocyte; melanoma; neoplastic; neoplastic cell; neurogenesis; notch protein; prevent; prognostic significance; promoter; public health relevance; relating to nervous system; targeted treatment; therapeutic target; therapy development; transdifferentiation; tumor; tumor growth; tumor progression; tumorigenesis

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）：