Cell-cell communication during melanoma development

黑色素瘤发育过程中的细胞间通讯

• 批准号: 8251130
• 负责人: Meenhard F Herlyn
• 金额: $ 26.33万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-05 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8251130
• 关键词: Address; Adipocytes; Area; Basement membrane; Cell Communication; Cell Differentiation process; Cell Lineage; Cells; Chemotactic Factors; Commit; Dermal; Dermis; Development; Down-Regulation; Employee Strikes; Environment; Epidermis; Epithelial Cells; Equilibrium; Funding; Hair; Hair follicle structure; Home environment; Human; Invaded; Investigation; Laboratories; Lead; Learning; Life; Ligands; Malignant - descriptor; Mediating; Melanoma Cell; Mesenchymal; Mesenchymal Stem Cells; Modeling; Neural Crest; Neurons; Notch and Wnt Signaling Pathway; Pathway interactions; Phenotype; Pigmentation physiologic function; Pigments; Plastics; Process; Property; Signal Transduction; Skin; Stem cells; Systems Biology; Testing; Tissues; Work; bone cell; cancer cell; cartilage cell; human SFRP4 protein; insight; keratinocyte; melanocyte; melanoma; neoplastic cell; notch protein; novel therapeutics; public health relevance; self-renewal; stem cell differentiation; stem cell niche; stemness; three-dimensional modeling

DESCRIPTION (provided by applicant): In this renewal application we extend previous studies on cell-cell interactions for both normal melanocytes and malignant melanoma cells. The laboratory has recently made two significant discoveries: i. We have found neural crest-like stem cells in the human dermis that differentiate into bona fide melanocytes which home to the epidermis, suggesting that they can serve as a continuous reservoir for epidermal pigment-producing melanocytes; ii. We discovered that Notch activation in pigment-producing melanocytes leads to de-differentiation towards a neural crest-like stem cell without malignant transformation, underscoring the plasticity of melanocytes. Our first working hypothesis is that dermal stem cell self-renewal is regulated through Notch and non-canonical Wnt signaling and is dependent on cellular localization in the context of the normal human dermis. Our second hypothesis is that melanocyte differentiation of dermal stem cells is regulated through Wnt signaling, in which signals change from the non-canonical to the canonical pathway. In the first aim we will define self-renewal of dermal neural crest-like stem cells, postulating that self-renewal is regulated through Wnt- and Notch-mediated signaling between stem cells and mesenchymal-like niche cells. We expect that Notch and Wnt signaling pathways cooperate to maintain stem cell self-renewal, and our studies are expected to reveal the mechanisms of pathway interactions. The striking similarities between dermal neural crest- like stem cells and melanoma cells underscore the significance of de-differentiation processes that cells undergo during transformation. In the second aim we will address differentiation of stem cells to melanocytes and the relocation of cells from the dermal to the epidermal skin compartment. For these studies we have developed a model of organotypic skin that allows investigations on the dynamic changes in neural crest-like stem cells as they separate from the niche to migrate through the basement membrane zone to the epidermis. During differentiation to melanocytes cells undergo profound phenotypic changes, thus understanding how these changes are induced may allow us to pursue the differentiation of malignant cells as a novel therapeutic strategy for melanoma. PUBLIC HEALTH RELEVANCE: We have discovered a new stem cell in human skin that has many properties in common with malignant cells. These stem cells are located in the lower compartment of the skin, the dermis, and can change to become melanocytes, neuronal cells, fat cells, bone cells or cartilage cells. We plan to study how they can be maintained in the skin, what it takes for them to migrate to the upper compartment of the skin, the epidermis, and what triggers their change to pigment-producing melanocytes. The stem cells share many molecules in common with melanoma cells but not with normal melanocytes, suggesting that melanoma cells should be compared to the stem cells and not the melanocytes. As we learn more about the stem cells, we begin to better understand how tumor cells migrate and invade through tissues.

描述（由申请人提供）：在此续签应用中，我们扩展了对正常黑色素细胞和恶性黑色素瘤细胞的细胞细胞相互作用的先前研究。该实验室最近发现了两个重大发现：i。我们发现人真皮中的神经rest状的干细胞分化为表皮所在的真正的黑素细胞，这表明它们可以作为产生表皮色素的黑素细胞的连续储层。 ii。我们发现，产生色素的黑素细胞中的缺口激活导致对神经rest样干细胞的差异化，而无需恶性转化，从而强调了黑素细胞的可塑性。我们的第一个工作假设是，皮肤干细胞的自我更新是通过Notch和非典型的Wnt信号调节的，并且取决于正常人真皮的背景下的细胞定位。我们的第二个假设是，通过Wnt信号传导调节真皮干细胞的黑素细胞分化，其中信号从非传统途径变为规范途径。在第一个目的中，我们将定义皮肤神经rest样干细胞的自我更新，并假定自我更新是通过干细胞和间充质样细胞之间的Wnt和Notch介导的信号来调节的。我们期望Notch和Wnt信号通路合作以保持干细胞自我更新，我们的研究有望揭示途径相互作用的机制。皮肤神经crest-like的干细胞和黑色素瘤细胞之间的惊人相似性强调了细胞在转化过程中经历的脱不同过程的重要性。在第二个目的中，我们将解决干细胞与黑素细胞的分化以及细胞从真皮到表皮皮肤区室的迁移。在这些研究中，我们开发了一种细胞型皮肤模型，该模型允许研究神经克雷斯特样干细胞的动态变化，因为它们与小众分离以通过地下膜区迁移到表皮。在分化为黑素细胞细胞的过程中会发生深刻的表型变化，因此了解这些变化是如何引起的，可能会使我们能够将恶性细胞的分化作为黑色素瘤的新型治疗策略。 公共卫生相关性：我们发现了人类皮肤中的一个新干细胞，该干细胞与恶性细胞具有许多共同的特性。这些干细胞位于皮肤，真皮的较低区室，可以变成黑色素细胞，神经元细胞，脂肪细胞，骨细胞或软骨细胞。我们计划研究如何将它们保持在皮肤中，将它们迁移到皮肤上部室，表皮以及触发其变化为产生色素的黑素细胞的原因。干细胞与黑色素瘤细胞共有许多共同点，但与正常的黑素细胞共同，表明应该将黑色素瘤细胞与干细胞而不是黑素细胞进行比较。随着我们更多地了解干细胞，我们开始更好地了解肿瘤细胞如何迁移并通过组织侵袭。