Identification and characterization of cancer cells of origin in the epidermis

描述(申请人提供)：癌症现在是这个国家的头号死因。许多最近开发的治疗方法都专注于控制现有肿瘤的生长，其中一些治疗方法已经将以前致命的癌症变成了可控制的情况。对肿瘤的研究导致了对现有疾病的深入描述，并识别了许多与癌症有关的基因。我们所知道的关于癌症的大部分知识都是基于现有的肿瘤，但对肿瘤发生背后的机制知之甚少。虽然我们对导致肿瘤形成的“基因冲击”和环境侮辱知道很多，但我们仍然不清楚哪些细胞是起源的癌细胞。任何细胞都能形成肿瘤吗？大多数成人组织含有各种各样的细胞类型，包括干细胞、转运放大细胞和分化细胞。许多人提出，成人干细胞是最有可能起源的癌细胞，因为它们在组织中寿命长，而且有自我更新或无限生长的能力。此外，许多被认为参与肿瘤发生的途径也被证明在成人干细胞的干细胞自我更新中发挥作用。然而，肿瘤发生的特定细胞类型的特性被这样一个事实所掩盖，即大多数肿瘤发生的研究都是利用预先存在的肿瘤组织，这是一种回溯性的方法。直到最近，还没有可用的工具来向组织中的特定细胞类型传递基因命中，以确定哪些细胞可以作为起源的癌细胞。此外，很少有模型系统能够将细胞从正在进行转化的组织中分离出来，以忠实地模拟自然的肿瘤发生。简而言之，积累的关于肿瘤发生的文献在很大程度上依赖于从未知细胞类型的未知机制靶向的转化组织中积累的数据。我们已经设计了一个模型系统，它采用了一种前瞻性的方法来识别起源的癌细胞。我们正在利用最新的工具和遗传技巧来针对表皮中的特定细胞类型进行基因打击，表皮是癌症最常见的靶组织。有了这些工具，我们正在将基因命中应用于干细胞或其运输放大后代，以探测更能作为起源癌细胞的细胞。此外，该模型系统允许在肿瘤起始或进展过程中的任何时间点对靶细胞进行纯化。这将使我们能够确定哪些基因受到肿瘤启动的影响，哪些基因在良性肿瘤启动与恶性肿瘤启动过程中发生了特异性改变。这些发现应该被证明不仅对癌症的治疗至关重要，甚至对癌症的预防也是至关重要的。此外，这项工作将挖掘关于干细胞及其后代的丰富信息，以及调控干细胞的途径是否被癌症利用。 公共卫生相关性：干细胞生物学和癌症的研究正在趋同。最近的数据表明，干细胞在癌症生物学的许多方面发挥着重要作用。这项应用旨在了解干细胞或其后代是否参与了癌症的启动。

DESCRIPTION (provided by applicant): Cancer is now the number one cause of death in this country. Many recently developed treatments have focused on managing the growth of existing tumors, and some of these treatments have turned previously lethal cancers into manageable conditions. The study of tumors has led to an in depth characterization of existing disease and the identification of many genes that are linked to cancer. The majority of what we know about cancer is based on existing tumors, but there is little knowledge on the mechanisms behind tumor initiation. While we know a great deal about the "genetic hits" and environmental insults that lead to tumor formation, it remains unclear which cells serve as cancer cells of origin. Can any cell make a tumor? Most adult tissues contain a wide variety of cell types including stem cells, transit-amplifying cells and differentiated cells. Many have proposed that adult stem cells are the most likely cancer cell of origin because of their longevity in the tissue and their capacity for self-renewal, or unlimited growth. Furthermore, many of the pathways thought to participate in tumorigenesis have also been shown to play a role in stem cell self-renewal in adult stem cells. However, the identity of the particular cell types targeted in tumorigenesis is obscured by the fact that most studies of tumorigenesis utilize pre-existing tumor tissue, a retrospective approach. Until recently there were no tools available to deliver genetic hits to specific cell types in a tissue to ask which could serve as cancer cells of origin. In addition, there are few model systems that allow for the isolation of cells from tissue undergoing transformation that faithfully mimic natural tumorigenesis. In short, the accumulated literature on tumorigenesis relies a great deal on data accumulated from transformed tissue targeted by an unknown mechanism in an unknown cell type. We have designed a model system that takes a prospective approach to identifying cancer cells of origin. We are taking advantage of the latest tools and genetic tricks to target genetic hits to particular cell types in the epidermis, the most common target tissue of cancer. With these tools, we are applying genetic hits to either stem cells or their transit-amplifying progeny to probe which is better able to serve as a cancer cell of origin. In addition, this model system allows for the purification of the targeted cells at any point during tumor initiation or progression. This will enable us to identify which genes are affected by tumor initiation, and which are specifically altered in benign versus malignant tumor initiation. These findings should prove critical to not only the treatment of cancer but potentially even the prevention of cancer. In addition, this work will unearth a wealth of information about stem cells and their progeny, and whether pathways that regulate stem cells are exploited by cancer. PUBLIC HEALTH RELEVANCE: The studies of stem cell biology and cancer are converging. Recent data suggests that stem cells play a prominent role in many aspects of cancer biology. This application aims to understand whether stem cells or their progeny are involved in the initiation of cancers.