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.

总体项目总结/摘要 癌症是一种由进化的基本力量驱动的进化和生态现象： 它提供了多层次选择的经典例子。 对于单个癌细胞，选择有利于肿瘤增殖；在宿主生物体水平上，选择有利于肿瘤增殖； 有利于癌症抑制。对癌症的全面了解取决于对这一基本原理的认识。 生物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 损伤的反应就规避了这些限制。 改变细胞水平进化的参数，导致恶性肿瘤并最终导致宿主死亡。 用多布赞斯基的话来说，有机体和细胞水平的进化在癌症中没有任何反馈。 除非从进化论的角度来看，生物学才有意义，这为我们提供了一个机会。 和生态理论对肿瘤进展和治疗反应亚利桑那癌症的使命。 和进化中心（ACE）旨在增进我们对癌症及其临床的基本了解 通过开发和应用进化和生态模型来治疗癌症 这一使命涵盖了癌症抑制机制和癌症的进化。 跨物种的易感性（项目 1）直至正常体细胞的进化（项目 2）和 癌细胞群（项目 3）。项目 1 将开发生物进化模型来预测癌症。 我们将使用癌症兽医数据库来测试这些预测。 超过 1,900 种动物物种的发病率，并检查 57 种哺乳动物物种的基因组以寻找证据 此外，项目 2 将测试项目 1 的模型预测。 项目 2 还将测量来自 57 个哺乳动物物种的原代细胞的癌症防御能力。 人类、小鼠和大象正常结肠和小肠组织进化的基本力量 解决癌症的一个基本但人们知之甚少的特性：癌症易感性的组织水平差异。 项目 3 将基于细胞级进化模型开发新的进化和生态指数 来自项目 1 的肿瘤，以预测 2 期和 3 期的长期治疗反应和患者生存率，化疗 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奠定基础，ACE 将支持癌症。 系统生物学联盟和不断发展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。