Identification and characterization of cancer cells of origin in the epidermis

描述（由申请人提供）：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集中在控制现有肿瘤的生长上，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疾病。对肿瘤的研究已经导致了对现有疾病的深入表征和对与癌症相关的许多基因的鉴定。我们对癌症的大部分了解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“基因打击”和环境损害了解很多，但仍不清楚哪些细胞是癌细胞的起源。任何细胞都能产生肿瘤吗？大多数成体组织含有多种细胞类型，包括干细胞、传递放大细胞和分化细胞。许多人提出，成体干细胞是最有可能的癌细胞来源，因为它们在组织中的寿命和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体干细胞的干细胞自我更新中发挥作用。然而，肿瘤发生中靶向的特定细胞类型的身份被以下事实所掩盖，即大多数肿瘤发生的研究利用预先存在的肿瘤组织，这是一种回顾性方法。直到最近，还没有工具可以将遗传命中传递到组织中的特定细胞类型，以确定哪些细胞可以作为癌细胞的起源。此外，很少有模型系统允许从经历转化的组织中分离细胞，其忠实地模拟天然肿瘤发生。简而言之，积累的关于肿瘤发生的文献大量依赖于从未知细胞类型中的未知机制靶向的转化组织积累的数据。我们设计了一个模型系统，采用前瞻性的方法来识别癌细胞的起源。我们正在利用最新的工具和遗传技巧，将遗传靶向表皮中的特定细胞类型，这是癌症最常见的靶组织。有了这些工具，我们将遗传命中应用于干细胞或其过渡扩增后代，以探测更能作为癌细胞起源的细胞。此外，该模型系统允许在肿瘤起始或进展期间的任何点纯化靶细胞。这将使我们能够确定哪些基因受到肿瘤起始的影响，以及哪些基因在良性肿瘤与恶性肿瘤起始中特异性改变。这些发现不仅对癌症的治疗至关重要，而且可能对癌症的预防也至关重要。此外，这项工作将发掘出大量关于干细胞及其后代的信息，以及调节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融合。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。本申请旨在了解干细胞或其后代是否参与癌症的起始。

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.