Arizona Cancer and Evolution Center (ACE)

总体项目摘要/摘要 巨蟹座是一种进化和生态现象，由进化的基本力量驱动： 突变、自然选择和基因漂移。它提供了一个多层次选择的经典例子。在这个层面上 在单个癌细胞中，选择有利于肿瘤的增殖；在宿主生物水平上，选择 支持癌症抑制。对癌症的全面了解取决于对这一基本原理的认识 紧张。生物体水平的调节机制决定了细胞水平的进化参数 例如体细胞突变率和对DNA损伤的反应。癌症规避了这些限制， 改变细胞水平的进化参数，导致恶性肿瘤和最终的宿主死亡。因此， 生物体和细胞水平的进化相互反馈。套用多布赞斯基的话说，癌症中没有什么 除了从进化论的角度来看，生物学是有意义的。这打开了一个机会。我们可以应用进化论 以及对肿瘤进展和治疗反应的生态学理论。亚利桑那州癌症协会的使命 和进化中心(ACE)是为了促进我们对癌症及其临床的基本了解 通过开发和应用癌症的进化和生态模型进行管理 生物学。这项任务跨越了癌症抑制机制和癌症进化的范围 跨物种的易感性(项目1)下至正常体细胞的进化(项目2)和 癌细胞群体(项目3)。项目1将开发预测癌症的生物进化模型 不同物种的发病率和癌症防御力。我们将使用兽医癌症数据库来测试这些预测 在1900多种动物中的发病率，并检查57种哺乳动物的基因组以寻找证据 对癌症选择性压力的适应。此外，项目2将检验项目1的S模型预测 同样来自57种哺乳动物的原代细胞中的癌症防御系统。项目2还将测量 人类、小鼠和大象正常结肠和小肠组织的基本进化力量 以解决癌症的一个基本但鲜为人知的属性：癌症易感性的组织水平差异。 项目3将开发新的进化和生态指数，基于年的细胞水平进化模型 来自项目1的肿瘤，用于预测2期和3期化疗的长期治疗反应和患者生存。 幼稚的结直肠癌。这些索引将首次提供一个分类系统， 社区可以用来区分具有不同进化动态的肿瘤，从而 为这一不断演变的疾病的临床管理提供了基础。ACE将支持巨蟹座 系统生物学联盟和不断增长的进化和癌症领域通过提供数据、分析工具、 模型、研讨会和教程，以促进这些资源的使用。

Overall Project Summary/Abstract Cancer is an evolutionary and ecological phenomenon driven by the fundamental forces of evolution: mutations, natural selection and genetic drift. It provides a classic example of multi-level selection. At the level of individual cancer cells, selection favors neoplastic proliferation; at the level of the host organism, selection favors cancer suppression. A full understanding of cancer hinges on an appreciation of this fundamental tension. Regulatory mechanisms at the organismal level determine evolutionary parameters at the cell level such as the somatic mutation rate and response to DNA damage. Cancer circumvents those constraints and changes the parameters of cell-level evolution, leading to malignancy and eventual host death. Thus, organismal and cell-level evolution feedback upon each other. To paraphrase Dobzhansky, nothing in cancer biology makes sense except in the light of evolution. This opens an opportunity. We may apply evolutionary and ecological theory to neoplastic progression and response to therapy. The mission of the Arizona Cancer and Evolution Center (ACE) is to advance our fundamental understanding of cancer and its clinical management through the development and application of evolutionary and ecological models to cancer biology. This mission spans scales from the evolution of cancer suppression mechanisms and cancer susceptibility across species (Project 1) down to the evolution of normal somatic cells (Project 2) and populations of cancer cells (Project 3). Project 1 will develop models of organismal evolution to predict cancer rates and cancer defenses across species. We will test those predictions using veterinary databases of cancer incidence in over 1,900 animal species, and examine the genomes of 57 mammalian species for evidence of adaptations to the selective pressure of cancer. In addition, Project 2 will test Project 1's model predictions of cancer defenses in primary cells from those same 57 mammalian species. Project 2 will also measure the fundamental forces of evolution in normal colonic and small intestine tissue from humans, mice and elephants to address a basic but poorly understood property of cancer: tissue-level differences in cancer susceptibility. Project 3 will develop novel evolutionary and ecological indices, based on models of cell-level evolution in neoplasms from Project 1, to predict long term therapeutic response and patient survival in stage 2&3, chemo- naïve colorectal cancers. These indices will provide, for the first time, a classification system that the community can use to draw distinctions between tumors with different evolutionary dynamics, and thereby provide a foundation for the clinical management of this evolving disease. ACE will support the Cancer Systems Biology Consortium and the growing field of evolution and cancer by providing data, analytical tools, models, workshops, and tutorials to facilitate the use of those resources.