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，通常称为“标志”。然而，问题 癌症发育的序列如何发展 - 从正常组织到致癌的组织到 癌前病变，最后是恶性肿瘤 - 尚未得到答复。经典，这些步骤是 归因于对离散遗传事件（例如驱动器突变）的顺序采集。但是，在 人类，管理癌症发展的克隆动力发生了多年，甚至在很大程度上看不见 在模型系统中，很难与特定的分子变化链接。这个标题无法解决 在组织结构的背景下的克隆动力学，无法解释大量的后果 正常组织中存在突变。我们的长期目标是将生态和进化原则应用于 癌症的启动和发展是为了测试是否获得了三个癌症的标志 不同的阶段每个阶段都具有不同的选择性压力和细胞竞争的表现和 合作。 没有比在皮肤上更容易获得投资的地方。对于皮肤癌，最重要的 致癌物是紫外线辐射。皮肤鳞状细胞癌（CUSCC）具有最容易的处理 从正常组织到明显的任何人类癌症的临床表征良好的进展序列 癌性病变（活化性角化病），侵入性癌。因此，它是建立生态的理想选择 癌症倡议和开发的进化范​​式在建模克隆动力学，通用性方面 组成和分子特征的动力学。 我们的中心假设是癌症倡议和发展分为三个阶段，每个阶段都有特定的 并识别克隆动力学。在第一阶段，紫外线暴露的组织破坏提供了允许的 外部驱动机制允许某些克隆经历很少长时间的环境 细胞分裂和营业额。这种巨大的克隆增加了克隆大小之间的差异 积累更大的遗传变化。第二阶段看到了内在机制的出现 在这种情况下，会议的突变允许选择克隆的选择，并定向扩展 有些克隆以牺牲其他克隆为代价。在第三阶段，一个或几个克隆逃脱了局部组织控制， 获得独特的适应性功能，并形成肿瘤。在新兴的肿瘤微环境中，选择 压力将促进恶性进化枝（或进化枝）的生态和分子多样化。我们的 方法使用串行体内定量成像，数学建模和深度的新型组合 单细胞分子询问，以辨别克隆动力学的生态和分子驱动因素，细胞至细胞 细胞竞争与合作以及克隆进化，从根本上产生了前所未有的观点 癌症开始。