Arizona Cancer and Evolution Center (ACE)

亚利桑那州癌症与进化中心 (ACE)

• 批准号: 10392864
• 负责人: Carlo Maley
• 金额: $ 157.9万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-12 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10392864
• 关键词: Address; Advanced Malignant Neoplasm; Aging; Animals; Area; Arizona; Biology; Body Size; Cancer Biology; Cell model; Cells; Cessation of life; Classification; Clinical; Clinical Management; Collaborations; Colon; Colorectal Cancer; Communication; Communities; Comparative Biology; Comparative Genomic Analysis; Computer Models; Coordination and Collaboration; DNA Damage; Data; Data Analytics; Databases; Development; Disease; Ecology; Ecosystem; Educational workshop; Elephants; Environment; Epidemiology; Evolution; Feedback; Foundations; Genetic Drift; Genome; Human; Incidence; Individual; Infrastructure; Institution; International; Life; Link; Longevity; Malignant Neoplasms; Mammals; Measures; Methods; Mission; Modeling; Mus; Mutation; Natural Selections; Nature; Neoplasms; Normal Cell; Oncology; Organism; Patients; Planet Earth; Population; Predisposition; Prevention; Property; Recording of previous events; Recurrence; Research; Resources; Risk; Small Intestines; Somatic Cell; Somatic Mutation; Source; System; Systems Biology; Testing; Time; Tissues; Veterinary Medicine; Veterinary Pathology; Work; analytical tool; anticancer research; base; cancer cell; cancer genomics; cancer prevention; comparative genomics; high risk; human tissue; improved; indexing; innovation; interest; life history; mathematical model; mortality; neoplastic; neoplastic cell; novel; novel strategies; outreach; predictive modeling; pressure; response; risk stratification; stem cells; success; theories; treatment response; tumor; tumor progression

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.

项目概要/摘要 癌症是一种进化和生态现象，由进化的基本力量驱动： 突变、自然选择和遗传漂变。它提供了一个经典的多级选择示例。级 在单个癌细胞中，选择有利于肿瘤增殖;在宿主生物体的水平上，选择有利于肿瘤增殖。 有利于抑制癌症对癌症的全面了解取决于对这一基本原理的理解。 张力生物体水平的调节机制决定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。癌症绕过了这些限制， 改变细胞水平进化的参数，导致恶性肿瘤和最终宿主死亡。因此，在本发明中， 生物体和细胞水平的进化相互反馈。套用杜布赞斯基的话，癌症 生物学是有意义的，除非从进化的角度来看。这是个机会我们可以应用进化论 和生态学理论来研究肿瘤的进展和对治疗的反应。亚利桑那癌症号的使命 和进化中心（ACE）是为了促进我们对癌症及其临床的基本理解， 通过开发和应用进化和生态模型来管理癌症 生物学这一使命跨越了从癌症抑制机制和癌症的演变到 跨物种的易感性（项目1）下降到正常体细胞的进化（项目2）， 癌细胞群（项目3）。项目1将开发生物进化模型以预测癌症 癌症发病率和癌症防御能力。我们将使用兽医癌症数据库来检验这些预测 在1，900多种动物物种中发病，并检查57种哺乳动物物种的基因组以寻找证据 适应癌症的选择压力。此外，项目2将测试项目1的模型预测， 癌症防御的原代细胞来自这57种哺乳动物。项目2还将衡量 人类、小鼠和大象的正常结肠和小肠组织中的基本进化力量 解决癌症的一个基本但知之甚少的特性：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，基于细胞水平的进化模型， 肿瘤，以预测长期治疗反应和患者生存的阶段2和3，化疗， 初治结肠直肠癌。这些指数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力学的肿瘤，从而 为这种不断发展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领域的进化和癌症，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。