Molecular definition of cancer cell-of-origin

癌细胞起源的分子定义

• 批准号: 9168198
• 负责人: Shangqin Guo
• 金额: $ 251.25万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9168198
• 关键词: Acceleration; Accounting; Acute Myelocytic Leukemia; Award; Behavior; Binding; Cancer Biology; Cancer Intervention; Cell Cycle; Cells; Chromatin; DNA Sequence Alteration; Data; Development; Disease; Epigenetic Process; Gene Expression; Genetic; Genomics; Goals; Hematopoietic; Hematopoietic System; Homeostasis; Human; Imagery; In Vitro; Logic; MLL-AF9; Malignant - descriptor; Malignant Neoplasms; Measurement; Modeling; Molecular; Mutation; Normal Cell; Oncogenes; Oncogenic; Perception; Phenotype; Physiological; Pluripotent Stem Cells; Solid Neoplasm; Somatic Cell; Speed; Stem cells; Surface; System; Testing; Therapeutic; Work; base; cancer cell; cancer initiation; epigenome; imaging genetics; in vivo; interdisciplinary approach; leukemia; mouse model; novel; progenitor; programs; transcription factor

Project Summary Why do some cells become malignant while most others do not? Can the cell-of-origin for cancer be identified based on specific features? How do we conceptualize such specific features within the framework of cancer biology? This proposal aims to provide answers for these questions. There are two prevailing, non- exclusive models to explain how cancers arise. One is that full transformation requires accumulation of multiple genetic mutations so that malignancy occurs only when all mutations have been acquired. The other is that mutations in rare stem cells cause malignancy. Recent technologic development has brought about contradicting evidence that is difficult for either of these models to explain, demanding a new conceptual framework to account for how malignancy is initiated. My previous work in tracking how somatic cells change their fate into pluripotent stem cells demonstrated that the epigenome responds to genetic insults differently when cell cycle is greatly accelerated. Based on this discovery, I propose a third model for how malignancy arises from normal cells: a transiently ultrafast cycling cell provides oncogenes with a permissive epigenetic context to induce malignancy. This hypothesis will be tested primarily using the hematopoietic system, in which the linage relationship, surface phenotype and cell cycle behaviors have all been well charted. The oncogene of choice is MLL-AF9, a fusion oncogene involved in human acute myeloid leukemia, which requires chromatin binding to initiate malignancy. We have established novel experimental approaches and obtained preliminary data that support malignant transformation is initiated from the fastest cycling hematopoietic progenitors in vitro. Because cancer is a disease in vivo, experimental strategies to vigorously define the cancer cell-of-origin in vivo are presented. New mouse models that will enable the visualization and measurement of cell cycle speed of leukemia initiating cells in vivo under homeostasis will be generated. Following our preliminary data supporting that ultrafast cycling cells display more accessible chromatin, we will formally test whether fast cell cycle promotes transformation by providing oncogenes with a more permissive chromatin context using genomic, genetic and imaging approaches. Finally, the generalizability of the central hypothesis will be tested using additional oncogenes and in solid tumor systems. Since the ultrafast cycling state could arise transiently in developmental, physiological, pathological or therapeutic conditions, this model makes a number of important predictions that can and will be experimentally tested. I anticipate to demonstrate that cell cycle acceleration fuels transformation not by generating more mutations, but by creating a more permissive chromatin context for oncogenic transcription factors to establish malignant gene expression programs. Overall, I aim to reveal a new logic for how oncogenes act and co-operate to induce malignancy, and to provide a fundamentally different perception for cancer initiation and intervention. The Director's New Innovator Award is the only support mechanism that can make achieving this goal possible.

项目摘要 为什么有些细胞会变成恶性细胞，而大多数细胞不会？癌症的起源细胞可以是 根据具体特点确定？我们如何在以下框架内对这些具体特征进行概念化 癌症生物学本提案旨在为这些问题提供答案。有两种流行的，非- 来解释癌症是如何产生的。一是全面转型需要积累多个 基因突变，只有当所有的突变都被获得时，恶性肿瘤才会发生。二是 罕见的干细胞突变会导致恶性肿瘤。最近的技术发展带来了 这两种模型都难以解释的矛盾证据，需要一个新的概念 框架来解释恶性肿瘤是如何开始的。我之前的工作是追踪体细胞如何变化 它们的命运变成多能干细胞表明，表观基因组对遗传损伤的反应不同 细胞周期大大加快。基于这一发现，我提出了第三个模型， 起源于正常细胞：一个短暂的超快循环细胞为癌基因提供了一个允许的表观遗传 诱发恶性肿瘤的背景。这一假设将主要使用造血系统进行测试，其中 其亲缘关系、表面表型和细胞周期行为都已被很好地描绘出来。癌基因 MLL-AF 9是一种与人类急性髓细胞白血病有关的融合癌基因，它需要染色质 结合引发恶性肿瘤我们已经建立了新的实验方法，并获得了初步的 支持恶性转化的数据是从最快循环的造血祖细胞开始的， 体外因为癌症是一种体内疾病，所以实验策略要大力定义癌细胞的起源， 在体内进行了介绍。新的小鼠模型将使细胞周期的可视化和测量成为可能 白血病起始细胞在体内稳态下的速度将被产生。根据我们的初步数据 支持超快循环细胞显示更易接近的染色质，我们将正式测试快速细胞是否 一个循环促进转化提供癌基因与更宽容的染色质背景下， 基因组、遗传和成像方法。最后，将检验中心假设的可推广性 使用另外的癌基因和在实体瘤系统中。由于超快循环状态可能是瞬时出现的， 在发育、生理、病理或治疗条件下，该模型产生许多 重要的预测，可以并将通过实验验证。我希望能证明细胞周期 加速不是通过产生更多的突变来推动转变，而是通过创造一个更宽容的环境， 染色质背景下的致癌转录因子，以建立恶性基因表达程序。 总的来说，我的目标是揭示一个新的逻辑如何癌基因的行为和合作，以诱导恶性肿瘤， 为癌症的发生和干预提供了一个根本不同的看法。导演的新创新者 奖励是实现这一目标的唯一支持机制。