Eco-evolutionary drivers of clonal dynamics during UV-induced skin carcinogenesis (PQ3)

紫外线诱发皮肤癌过程中克隆动力学的生态进化驱动因素（PQ3）

• 批准号: 10177427
• 负责人: Joel Brown
• 金额: $ 64万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10177427
• 关键词: Actinic keratosis; Architecture; Binding; Biological Models; Cancer Center; Carcinogens; Carcinoma; Cell division; Cells; Characteristics; Chronic; Clinical; Clonal Evolution; Development; Ecology; Environment; Epithelial; Event; Genetic; Genetic Transcription; Genomics; Goals; Heritability; Heterogeneity; Human; Human Cloning; Individual; Investigation; Lesion; Ligands; Link; Malignant - descriptor; Malignant Neoplasms; Mathematics; Measures; Mediating; Modeling; Molecular; Molecular Genetics; Mutation; Normal tissue morphology; Oncology; Pathogenicity; Phase; Proliferating; Running; Skin; Skin Cancer; Skin Carcinogenesis; Skin Carcinoma; Stress; Testing; Time; Tissues; Transplantation; UV Radiation Exposure; UV induced; Ultraviolet Rays; Variant; Work; cancer initiation; carcinogenesis; driver mutation; experience; fitness; in vivo; mathematical model; molecular dynamics; multidisciplinary; novel; premalignant; pressure; quantitative imaging; receptor; single cell sequencing; skin squamous cell carcinoma; trait; tumor; tumor microenvironment

ABSTRACT Cancers have readily-defined characteristics often referred to as “hallmarks”. Nevertheless, the question of how the sequence of cancer development progresses -- from normal tissue to carcinogen-damaged tissue to precancerous lesion and finally to malignant tumors – remains unanswered. Classically, these steps are attributed to the sequential acquisition of discrete genetic events such as driver mutations. However, in humans, the clonal dynamics governing cancer development happen over years, remain largely invisible even in model systems, and have been difficult to link to specific molecular changes. This rubric fails to account for clonal dynamics in the context of tissue architecture and fails to explain the consequences of large numbers of mutations present in normal tissue. Our long-term goal is to apply ecological and evolutionary principles to cancer initiation and development in order to test whether the hallmarks of cancer are acquired in three distinct phases each with distinct selective pressures and manifestations of cell competition and cooperation. Nowhere is this more accessible to investigation than in skin. For skin carcinomas, the most important carcinogen is ultraviolet radiation. Cutaneous squamous cell carcinoma (cuSCC) has the most tractable and clinically well-characterized progression sequence of any human cancer, from normal tissue, to a distinct precancerous lesion (the actinic keratosis), to invasive carcinoma. Therefore, it is ideal for establishing an eco- evolutionary paradigm of cancer initiation and development with respect to modelling clonal dynamics, genetic composition and the dynamics of molecular traits. Our central hypothesis is that cancer initiation and development occurs in three phases, each with specific and recognizable clonal dynamics. In the first phase, tissue disruption from UV exposure provides a permissive environment where extrinsically-driven mechanisms allow for some clones to experience unusually long runs of cell division and turnover. This greatly increases the variance among clone sizes with larger clones accumulating greater heritable variation. The second phase sees the emergence of intrinsic mechanisms where mutations that confer a competitive advantage allow for clonal selection with directed expansion of some clones at the expense of others. In the third phase, one or several clones escape local tissue control, acquire a distinct fitness function, and form tumors. Within the emerging tumor microenvironments, selection pressures will promote ecological and molecular diversification of the malignant clade (or clades). Our approach uses novel combinations of serial in-vivo quantitative imaging, mathematical modeling, and deep single-cell molecular interrogation to discern the ecological and molecular drivers of clonal dynamics, cell-to- cell competition and cooperation, and clonal evolution, producing a fundamentally unprecedented view of cancer initiation.

抽象的 癌症具有易于定义的特征，通常被称为“标志”。 癌症发展的顺序是如何进行的——从正常组织到致癌物质损伤的组织再到 癌前病变并最终发展为恶性肿瘤——传统上，这些步骤仍然没有答案。 归因于离散遗传事件（例如驱动突变）的连续获得。 对于人类来说，控制癌症发展的克隆动态多年来一直在发生，即使在很大程度上仍然是不可见的 在模型系统中，并且很难与特定的分子变化联系起来，这个标题未能解释。 组织结构背景下的克隆动力学，无法解释大量克隆的后果 我们的长期目标是将生态和进化原理应用于正常组织中。 癌症的发生和发展，以测试癌症的特征是否是通过三种方式获得的 不同的阶段，每个阶段都有不同的选择压力和细胞竞争的表现 合作。 对于皮肤癌来说，这是最容易进行研究的地方，这是最重要的。 皮肤鳞状细胞癌（cuSCC）是最容易治疗和治疗的致癌物质。 任何人类癌症从正常组织到独特的临床特征的进展顺序 因此，它是建立生态的理想选择。 癌症发生和发展的进化范式涉及克隆动力学、遗传建模 分子特征的组成和动力学。 我们的中心假设是癌症的发生和发展分三个阶段，每个阶段都有特定的 在第一阶段，紫外线照射造成的组织破坏提供了许可。 外部驱动机制允许一些克隆经历异常长时间的环境 细胞分裂和更新大大增加了克隆大小与较大克隆之间的差异。 积累更大的遗传变异；第二阶段是内在机制的出现。 其中赋予竞争优势的突变允许通过定向扩增进行克隆选择 一些克隆以牺牲其他克隆为代价在第三阶段，一个或多个克隆逃脱了局部组织的控制， 获得独特的适应功能，并在新兴的肿瘤微环境中形成肿瘤。 压力将促进恶性进化枝（或多个进化枝）的生态和分子多样化。 该方法采用连续体内定量成像、数学建模和深度学习的新颖组合 单细胞分子询问，以辨别克隆动力学、细胞间的生态和分子驱动因素 细胞竞争与合作，以及克隆进化，产生了一种根本上原始的观点 癌症的发生。