Project 2: Understanding the Cellular Origins of Melanoma

项目摘要 黑色素瘤是一种早期发现就可以手术治愈的癌症，很难与之区分 人类皮肤上常见的良性色素沉着斑(Nevi)，这种情况会导致不必要的 良性痣的切除，以及未能发现一些正在演变的黑色素瘤。有趣的是，最频繁的 黑色素瘤的致癌突变--BRAF的激活--也是大多数色素痣的原因。然而，与黑色素瘤不同， 雀斑自然停止生长。这一解释被归因于“癌基因导致的衰老”， 但各种观察表明，抑制nevi的不是细胞自主衰老，而是 更可逆的是痣细胞之间的相互作用，以及这些细胞与其环境之间的相互作用。是这样的 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 控制和大小的动态平衡。使用可诱导的BRAF突变小鼠模型，我们最近进行了观察 色素痣不仅由色素细胞组成，还由一种新的黑素细胞群组成，形成了一层“面纱”。 与血统关系的存在一致，这可能是这种 反馈策略。 在这个项目中，我们将研究这些细胞类型在产生nevi和nevi的小鼠模型中的作用。 黑色素瘤，试图确定生长控制的本质和黑色素瘤细胞 逃离它。我们将结合数学建模来开发假设，以解释 这些模型中痣和黑色素瘤发展的时空动力学和空间统计，包括 解释同一小鼠黑色素痣和黑色素瘤发展的潜在分支。我们会 使用时间进程单细胞RNA测序来识别潜在的正反馈和负反馈调节因子 推动这样的模型，并将进行实验，以测试基于模型的预测，关于 这样的分子发挥作用。最后，我们将调查发生的自发回归现象 以寻找免疫系统如何有效识别黑素细胞的线索 过度生长。这些信息将有助于开发新的预防和治疗策略 毁灭性的疾病。

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.