BACKGROUND Many cancers arise from mutations in cells within epithelial tissues. Mutations manifesting at the subcellular level influence the structure and function of the tissue resulting in cancer. Previous work has proposed how cell level properties can lead to mutant cell invasion, but has not incorporated detailed subcellular modelling RESULTS: We present a framework that allows the straightforward integration and simulation of SBML representations of subcellular dynamics within multiscale models of epithelial tissues. This allows us to investigate the effect of mutations in subcellular pathways on the migration of cells within the colorectal crypt. Using multiple models we find that mutations in APC, a key component in the Wnt signalling pathway, can bias neutral drift and can also cause downward invasion of mutant cells in the crypt. CONCLUSIONS Our framework allows us to investigate how subcellular mutations, i.e. knockouts and knockdowns, affect cell-level properties and the resultant migration of cells within epithelial tissues. In the context of the colorectal crypt, we see that mutations in APC can lead directly to mutant cell invasion.

中文翻译：

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模拟亚细胞突变对结直肠隐窝中细胞迁移的影响。

背景技术许多癌症源自上皮组织内细胞的突变。在亚细胞水平上表达的突变影响组织的结构和功能，导致癌症。先前的工作提出了细胞水平特性如何导致突变细胞侵袭的方法，但尚未纳入详细的亚细胞模型。结果：我们提出了一个框架，该框架允许在上皮组织的多尺度模型内直接整合和模拟SBML表示的亚细胞动力学。这使我们能够研究亚细胞途径中的突变对结直肠隐窝内细胞迁移的影响。使用多种模型，我们发现APC中的突变是Wnt信号通路的关键组成部分，它可以偏向中性漂移，还可以导致隐窝中突变细胞的向下侵袭。结论我们的框架使我们能够研究亚细胞突变（即敲除和敲低）如何影响细胞水平特性以及上皮组织内细胞的迁移。在大肠隐窝的背景下，我们看到APC中的突变可直接导致突变细胞入侵。