跨生物学尺度的突变风险的机制解释
A mechanistic interpretation of mutation risk across biological scales
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中文总结 AI 辅助
本研究通过智能体模型揭示突变-分化平衡如何决定细胞数量对癌症风险的影响，为跨尺度的癌症风险异速生长提供机制解释。
中文摘要 AI 辅助
哺乳动物癌症风险的异速生长具有尺度特异性，因为种间、种内和器官间的癌症风险缩放模式彼此不同。尽管癌症风险在物种间随体型增大几乎不变，但已知体型较大的同种个体患癌风险更高。癌症风险随年龄和寿命的变化趋势也已在人类和其他物种中得到记录。然而，哺乳动物普遍共享发育特征，细胞分裂和分化这两个孪生过程是发育动力学的核心。在本研究中，我们假设对这些过程跨生物学尺度的更深入理解可能有助于更清晰地理解癌症风险的异速生长。我们开发了一个基于智能体的模型，其中细胞区室从一个细胞生长到目标大小。我们评估了发育动力学如何随区室大小缩放并影响突变积累。我们的数据确定了参数空间中的特定区域，在这些区域中，中性突变的积累随细胞数量增加而增加，同时为这种行为提供了机制解释。非中性突变的积累揭示了突变与分化之间在细胞适应性上的有趣拮抗作用，这可能改变特定发育策略的可行性。我们的模型能够在其参数空间的不同部分产生广泛的癌症风险异速生长趋势，反映了跨生物学尺度观察到的异质性。我们的结果提供了一个理论框架，使我们能够阐明突变-分化平衡的条件，在这些条件下，拥有更多细胞确实会导致更高的癌症风险，并且重要的是，在哪些条件下不会。
英文摘要
The allometry of cancer risk in mammals is scale-specific, as the inter-specific, intra-specific, and inter-organ patterns in cancer risk scaling are distinct from each other. While cancer risk barely changes with increasing body sizes across species, larger conspecifics are known to be at a higher risk of cancer. Cancer risk trends with age and lifespan have likewise been documented in humans and other species. Nevertheless, mammals broadly share developmental features, and the twin processes of cell division and differentiation are central to developmental dynamics. In this study, we suppose that a better understanding of these processes across biological scales could lead to a clearer understanding of cancer risk allometries. We develop an agent-based model in which a cell compartment grows from one cell to a target size. We assess how developmental dynamics scale with compartment size and influence mutation accumulation. Our data identify specific regions of the parameter space where the accumulation of neutral mutations increases with cell number, while providing a mechanistic explanation for such behavior. The accumulation of non-neutral mutations reveals an interesting antagonism in cell fitness between mutation and differentiation, which could change the viability of a given developmental strategy. Our model is able to produce a wide range of trends in cancer risk allometries in different parts of its parameter space, reflecting the observed heterogeneity across biological scales. Our results provide a theoretical framework that allows us to elucidate the conditions of mutation-differentiation balance under which having more cells does lead to higher cancer risk, and importantly, the conditions under which it does not.
发表机构
- Indian Institute of Science Education and Research (IISER), Pune, India（印度科学教育研究所）
- University of Texas at Austin, US（德克萨斯大学奥斯汀分校）
- Indian Institute of Science (IISc), Bengaluru, India（印度科学学院）
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