Molecular definition of cancer cell-of-origin

项目摘要 为什么有些细胞会变得恶性，而大多数其他细胞不会？癌症的起源细胞可能是 根据特定特征进行识别？我们如何在以下框架中概念化这些特定功能 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 独家模型来解释癌症是如何产生的。其一，全面转型需要多次积累 基因突变，只有当所有突变都已获得时，才会发生恶性肿瘤。另一种是， 罕见干细胞的突变会导致恶性肿瘤。最近的技术发展带来了 与这两个模型都难以解释的证据相矛盾，需要一个新的概念 一个框架，以说明恶性肿瘤是如何启动的。我之前在追踪体细胞如何变化方面的工作 它们进入多能干细胞的命运表明，表观基因组对遗传侮辱的反应是不同的。 当细胞周期大大加快时。基于这一发现，我提出了关于恶性程度的第三个模型 起源于正常细胞：短暂的超快周期细胞为癌基因提供了允许的表观遗传学 引发恶变的背景。这一假设将主要使用造血系统进行验证，在该系统中 线形关系、表面表型和细胞周期行为都已被很好地描绘出来。癌基因 首选的是MLL-AF9，这是一种与人类急性髓系白血病有关的融合癌基因，需要染色质 具有引发恶性的约束力。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来自最快周期的造血祖 体外培养。因为癌症是体内的一种疾病，所以实验策略大力确定癌细胞的起源 在活体内的研究进展。新的小鼠模型将使细胞周期可视化和测量成为可能 体内白血病启动细胞在体内动态平衡的速度会产生。根据我们的初步数据 支持超快周期细胞显示更多可及染色质，我们将正式测试快速细胞 Cycle通过为癌基因提供更宽松的染色质环境来促进转化 基因组、遗传和成像方法。最后，将检验中心假设的概括性 在实体肿瘤系统中使用额外的致癌基因。由于超快循环状态可能会瞬间出现 在发育、生理、病理或治疗条件下，该模型产生了许多 能够而且将会得到实验检验的重要预测。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型，而是通过创造更宽松的 染色质背景下的致癌转录因子建立恶性基因表达程序。 总而言之，我的目标是揭示一种新的逻辑，即癌基因是如何作用和合作来诱发恶性肿瘤的，并 为癌症的启动和干预提供了一种根本不同的看法。主任的新创新者 奖励是实现这一目标的唯一支持机制。

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.