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）：在本次更新申请中，我们扩展了之前对正常黑素细胞和恶性黑素瘤细胞的细胞间相互作用的研究。该实验室最近取得了两项重大发现：我们在人类真皮中发现了类似神经嵴的干细胞，可以分化为真正的黑素细胞，并归巢于表皮，这表明它们可以作为表皮色素生成黑素细胞的连续储存库；二.我们发现，产生色素的黑素细胞中的Notch激活导致去分化为神经嵴样干细胞，而没有恶性转化，这强调了黑素细胞的可塑性。我们的第一个工作假设是，真皮干细胞的自我更新是通过 Notch 和非经典 Wnt 信号传导来调节的，并且依赖于正常人类真皮中的细胞定位。我们的第二个假设是真皮干细胞的黑素细胞分化是通过 Wnt 信号传导调节的，其中信号从非规范途径转变为规范途径。在第一个目标中，我们将定义真皮神经嵴样干细胞的自我更新，假设自我更新是通过干细胞和间充质样利基细胞之间 Wnt 和 Notch 介导的信号传导来调节的。我们期望Notch和Wnt信号通路合作维持干细胞的自我更新，我们的研究有望揭示通路相互作用的机制。真皮神经嵴样干细胞和黑色素瘤细胞之间惊人的相似性强调了细胞在转化过程中经历的去分化过程的重要性。在第二个目标中，我们将解决干细胞向黑素细胞的分化以及细胞从真皮到表皮隔室的重新定位。在这些研究中，我们开发了一种器官型皮肤模型，可以研究神经嵴样干细胞从微环境分离并通过基底膜区迁移到表皮时的动态变化。在分化为黑色素细胞的过程中，细胞经历了深刻的表型变化，因此了解这些变化是如何诱导的可能使我们能够将恶性细胞的分化作为黑色素瘤的一种新的治疗策略。 公共健康相关性：我们在人类皮肤中发现了一种新的干细胞，它具有许多与恶性细胞相同的特性。这些干细胞位于皮肤的下层，即真皮，可以转变为黑素细胞、神经元细胞、脂肪细胞、骨细胞或软骨细胞。我们计划研究它们如何维持在皮肤中、它们如何迁移到皮肤的上层、表皮，以及是什么触发它们转变为产生色素的黑素细胞。干细胞与黑色素瘤细胞共享许多相同的分子，但与正常黑色素细胞不同，这表明黑色素瘤细胞应该与干细胞而不是黑色素细胞进行比较。随着我们对干细胞了解更多，我们开始更好地了解肿瘤细胞如何迁移和侵入组织。