Project 2: Understanding the Cellular Origins of Melanoma

项目 2：了解黑色素瘤的细胞起源

• 批准号: 10392898
• 负责人: Anand K Ganesan
• 金额: $ 42.83万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10392898
• 关键词: Ablation; Address; Affect; Alleles; BRAF gene; Behavior; Benign; Cells; Clinical; Communities; Data; Development; Diffuse; Disease; Environment; Event; Excision; Failure; Feedback; Frequencies; Growth; Homeostasis; Human; Immune; Immune system; Immunohistochemistry; Immunotherapy; Individual; Infiltration; Label; Lasers; Lead; Learning; Lesion; Ligands; Light; Malignant Neoplasms; Melanocytic nevus; Melanoma Cell; Modeling; Mole the mammal; Molecular; Morphology; Mus; Mutation; Nature; Nevi and Melanomas; Nevus; Nevus Cell; Normal tissue morphology; Oncogenes; Oncogenic; Operating System; Operative Surgical Procedures; PTEN gene; Pigments; Play; Population; Prevention; Prevention approach; Process; Production; Role; Series; Signal Pathway; Signaling Molecule; Skin; Spottings; Testing; Therapeutic; base; cell type; differential expression; experimental study; live cell imaging; loss of function mutation; mathematical model; melanocyte; melanoma; mouse model; mutant mouse model; novel; novel strategies; prevent; programs; receptor; response; self-renewal; senescence; single-cell RNA sequencing; spatiotemporal; statistics; therapy resistant; time use; transcriptome; transcriptomics; tumor; ultraviolet irradiation

Project Summary Melanoma, a cancer that can be surgically cured when detected early, can be difficult to distinguish from common, benign pigmented spots (nevi) that develop on human skin, a situation that leads to the unnecessary excision of benign nevi and the failure to detect some evolving melanomas. Intriguingly, the most frequent oncogenic mutation in melanoma—activation of BRAF—is also the cause of most nevi. Yet, unlike melanoma, nevi spontaneously growth-arrest. The explanation has been attributed to “oncogene-induced senescence”, but a variety of observations indicate that what holds nevi in check is not cell-autonomous senescence, but rather reversible interactions among nevus cells, and between those cells and their environment. Such interactions resemble the intra-lineage feedback mechanisms used by many normal tissues to achieve growth control and size homeostasis. Using an inducible Braf-mutant mouse model, we recently made the observation that nevi are not only composed of pigmented cells but also a novel melanocyte population that forms a “veil” around the pigmented cells, consistent with the existence of lineage relationships that could underlie such a feedback strategy. In this project, we will investigate the role of these cell types in mouse models that produce both nevi and melanoma, seeking to identify both the nature of growth control and the means by which melanoma cells escape from it. We will integrate mathematical modeling to develop hypotheses that can explain the spatiotemporal dynamics and spatial statistics of nevus and melanoma development in these models, including potential bifurcations that account for the development of both nevi and melanoma in the same mouse. We will use time-course single cell RNA-sequencing to identify potential positive and negative feedback regulators that drive such models, and will carry out experiments to test model-based predictions concerning the roles that such molecules play. Finally, we will investigate the phenomenon of spontaneous regression, which occurs with both mouse and human nevi, for clues into how the immune system efficiently recognizes melanocyte overgrowth. Such information will be useful in developing new prevention and therapeutic strategies for this devastating disease.

项目摘要 黑色素瘤是一种在早期发现时可以手术治愈的癌症， 常见的良性色素斑（痣），在人类皮肤上发展，这种情况会导致不必要的 切除良性痣和未能检测到一些发展中的黑色素瘤。有趣的是，最常见的 黑色素瘤中的致癌突变-BRAF的激活-也是大多数痣的原因。然而，与黑色素瘤不同， 痣自发生长停止。这种解释被归因于“癌基因诱导的衰老”， 但各种观察表明，控制痣的不是细胞自主衰老， 痣细胞之间以及这些细胞与环境之间的相互作用是可逆的。等 相互作用类似于许多正常组织用来实现生长的谱系内反馈机制 控制和大小稳态。最近，我们使用一种可诱导的Braf突变小鼠模型， 痣不仅由色素细胞组成，而且还由一种新的黑素细胞群组成， 周围的色素细胞，与存在的血统关系，可能是这样一个一致的， 反馈策略 在这个项目中，我们将研究这些细胞类型在小鼠模型中的作用， 黑色素瘤，寻求确定生长控制的性质和黑色素瘤细胞 我们将整合数学建模，以开发可以解释 这些模型中痣和黑色素瘤发展的时空动态和空间统计，包括 在同一只小鼠中，痣和黑色素瘤的发展可能存在分歧。我们将 使用时程单细胞RNA测序来鉴定潜在的正反馈和负反馈调节因子， 驱动这些模型，并将进行实验，以测试基于模型的预测， 这样的分子发挥作用。最后，我们将研究自发回归现象， 为了寻找免疫系统如何有效识别黑素细胞的线索， 过度生长这些信息将有助于制定新的预防和治疗策略， 毁灭性的疾病