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把以前致命的癌症变成了可控的状况。对肿瘤的研究已经导致了对现有疾病的深入表征，并确定了许多与癌症有关的基因。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“基因冲击”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。任何细胞都能形成肿瘤吗？大多数成人组织包含各种各样的细胞类型，包括干细胞，转运扩增细胞和分化细胞。许多人提出，成体干细胞最有可能是癌细胞的起源，因为它们在组织中的寿命长，具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体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身份被大多数肿瘤发生研究利用预先存在的肿瘤组织这一事实所掩盖，这是一种回顾性的方法。直到最近，还没有可用的工具来对组织中的特定细胞类型进行基因攻击，以询问哪些细胞可能是癌细胞的起源。此外，很少有模型系统允许从正在进行转化的组织中分离细胞，忠实地模拟自然肿瘤发生。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由未知细胞类型中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基因技巧，将基因攻击的目标对准表皮上的特定细胞类型，表皮是癌症最常见的目标组织。有了这些工具，我们正在对干细胞或它们的转运扩增后代应用基因命中，以探索哪一个更能作为癌细胞的起源。此外，该模型系统允许在肿瘤起始或进展过程中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，哪些基因在良性肿瘤起始和恶性肿瘤起始中被特异性改变。这些发现不仅对癌症的治疗至关重要，甚至可能对癌症的预防也至关重要。此外，这项工作将揭示关于干细胞及其后代的丰富信息，以及调节干细胞的途径是否被癌症利用。

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.