纤维细胞外基质中异型癌细胞群的多尺度动力学
Multiscale dynamics of a heterotypic cancer cell population within a fibrous extracellular matrix
摘要：
局部癌细胞侵袭是涉及许多细胞和组织相互作用的复杂过程，并且是转移性扩散的重要先决条件，转移性扩散是癌症相关死亡的主要原因。在许多不同的时间和空间尺度上，局部侵袭的第一阶段是基质降解酶（MDE）的分泌和由此导致的细胞外基质（ECM）的降解。这个过程创造了细胞可以侵入的空间，从而扩大了肿瘤。随着肿瘤恶性程度的增加，癌细胞具有突变成次级细胞亚群的能力，从而产生异质性肿瘤。这种新的细胞亚群通常具有更高的侵袭性，并允许肿瘤更快地扩散。基于最近在Shuttleworth和Trucu（2019）中引入的纤维ECM中癌症侵袭的多尺度建模框架，在本文中，我们考虑了由两个癌细胞群混合的异型肿瘤局部侵袭的过程。为此，我们通过两部分建模框架的发展解决了组织尺度癌症动力学和细胞尺度分子过程之间的双重反馈联系，该框架关键地结合了在两相细胞外基质内发生的定向纤维的多尺度动态再分布，并将其与探索关键基质的多尺度前沿动力学相结合。降解酶沿着肿瘤界面的分子过程，驱动癌症边界的移动。建模框架将伴随着计算结果，探索底层纤维网络对癌症侵袭整体模式的影响。
英文摘要：
Local cancer cell invasion is a complex process involving many cellular and tissue interactions and is an important prerequisite for metastatic spread, the main cause of cancer related deaths. Occurring over many different temporal and spatial scales, the first stage of local invasion is the secretion of matrix-degrading enzymes (MDEs) and the resulting degradation of the extra-cellular matrix (ECM). This process creates space in which the cells can invade and thus enlarge the tumour. As a tumour increases in malignancy, the cancer cells adopt the ability to mutate into secondary cell subpopulations giving rise to a heterogeneous tumour. This new cell subpopulation often carries higher invasive qualities and permits a quicker spread of the tumour. Building upon the recent multiscale modelling framework for cancer invasion within a fibrous ECM introduced in Shuttleworth and Trucu (2019), in this paper we consider the process of local invasion by a heterotypic tumour consisting of two cancer cell populations mixed with a two-phase ECM. To that end, we address the double feedback link between the tissue-scale cancer dynamics and the cell-scale molecular processes through the development of a two-part modelling framework that crucially incorporates the multiscale dynamic redistribution of oriented fibres occurring within a two-phase extra-cellular matrix and combines this with the multiscale leading edge dynamics exploring key matrix-degrading enzymes molecular processes along the tumour interface that drive the movement of the cancer boundary. The modelling framework will be accompanied by computational results that explore the effects of the underlying fibre network on the overall pattern of cancer invasion.
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