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

摘要 癌症具有容易定义的特征，通常被称为“特征”。尽管如此，关于 癌症发展的顺序是如何进展的--从正常组织到致癌物受损组织，再到 癌前病变，最后到恶性肿瘤--仍然没有答案。传统上，这些步骤是 归因于连续获取离散遗传事件，如驱动程序突变。但是，在 人类，多年来控制癌症发展的克隆动力，甚至在很大程度上仍然是看不见的。 在模型系统中，已经很难将其与特定的分子变化联系起来。这个题目没有考虑到 组织结构背景下的克隆动力学，未能解释大量 突变存在于正常组织中。我们的长期目标是将生态和进化原则应用于 癌症的发生和发展，以测试癌症的特征是否在三个月内获得 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。 没有任何地方比皮肤更容易被研究。对于皮肤癌来说，最重要的 致癌物质是紫外线辐射。皮肤鳞状细胞癌(CuSCC)是最容易治疗和 任何人类癌症的临床特征良好的进展序列，从正常组织到明显的 癌前病变(光化性角化病)，到浸润性癌。因此，它是建立一个生态环境的理想选择。 关于模拟克隆动力学和遗传学的癌症发生和发展的进化范式 分子特征的组成和动态。 我们的中心假设是癌症的发生和发展有三个阶段，每个阶段都有特定的 和可辨认的克隆动力学。在第一阶段，紫外线照射对组织的破坏提供了一个允许的 外部驱动机制允许某些克隆人经历异常长时间运行的环境 细胞分裂和周转。这大大增加了克隆大小与较大克隆之间的差异 积累了更大的可遗传变异。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克隆选择通过定向扩展 一些克隆人以牺牲其他人为代价。在第三阶段，一个或几个克隆逃避局部组织控制， 获得独特的健身功能，并形成肿瘤。在新兴的肿瘤微环境中，选择 压力将促进恶性分支(或分支)的生态和分子多样化。我们的 该方法使用了一系列体内定量成像、数学建模和深度成像的新组合 单细胞分子询问以辨别克隆动力学、细胞到细胞的生态和分子驱动因素 细胞竞争与合作，以及克隆进化，产生了一种从根本上前所未有的观点 癌症的开端。

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.