Multiscale Modelling of Adhesion, Tumour Heterogeneity and Immune Response in Breast Cancer Invasion

了解癌症侵入人体的复杂机制仍然是最大的科学挑战之一。这种异型细胞过程的核心是癌症侵袭的生物学多尺度特征，其动力学发生在几个相互关联的空间尺度上，从细胞尺度的分子信号传导到组织尺度的细胞群体活动。此外，过去几十年的研究表明，免疫反应在癌症侵袭中起着重要作用。由癌症发展的异质性自然诱导，肿瘤异质性通过与肿瘤微环境中促进和抑制肿瘤的免疫细胞的相互作用进一步增强。另一方面，细胞粘附（在各种免疫细胞的作用下）在肿瘤扩散中起主要作用。本研究旨在通过发展新的多尺度模型，重点关注各种肿瘤浸润免疫细胞直接影响下的细胞粘附和肿瘤异质性，从而更深入地了解癌症的侵袭。这是一个跨学科项目，由Trucuand Eftimie博士联合领导，并与临床专家Andrew Evans教授（邓迪NinewellsHospital）和Alastair Thompson教授（MD anderson癌症中心，美国德克萨斯大学）合作开展。目的1：通过探索组织尺度肿瘤运动与钙敏感受体和钙离子的细胞尺度相互作用之间的关系，建立一种新的多尺度移动边界模型，该模型可以解释细胞-细胞粘附；目的2：通过考虑肿瘤浸润性免疫细胞以及免疫炎性和癌症相关成纤维细胞的作用，研究肿瘤异质性。目标3：利用成像数据（由Evans教授和thompson教授提供）开发一种模型校准程序，旨在通过这种方式捕捉乳腺癌肿瘤的真实边界。目标4：通过多尺度分析概念，如三尺度收敛，分析研究目标1和2中开发的模型

Understanding the complex mechanisms of cancer invasion in the human body remains one of thegreatest scientific challenges. At the core of this heterotypic cell process stays the biologically multiscalecharacter of cancer invasion, whose dynamics takes place on several interlinked spatial scales, rangingfrom cell-scale molecular signaling to tissue-scale cell population activity. Moreover, research overthe past decades has shown that the immune response plays an important role within cancer invasion.Naturally induced by the heterotypic character of cancer development, tumour heterogeneity is furtherpotentiated by the interactions with tumour-promoting and tumour-suppressing immune cells withinthe tumour microenvironment. On the other hand, cell adhesion (under the impact of various immunecells) plays a major role in tumour spread.This research aims to provide a deeper understanding of cancer invasion through the development ofnovel multiscale modelling focused on cell-adhesion and tumour heterogeneity under the direct impactof various tumour-infiltrating immune cells. This is an interdisciplinary project led jointly by Dr. Trucuand Dr. Eftimie and carried out in collaboration with clinical experts, Prof. Andrew Evans (NinewellsHospital Dundee) and Prof Alastair Thompson (MD Andreson Cancer Centre, University of Texas, USA).Aims and Objectives:Objective 1: Develop a novel multiscale moving boundary model that accounts for cell-cell adhesion byexploring the correlation between tissue-scale cancer motility and cell-scale interactions of calciumsensing receptors and calcium ions;Objective 2: Investigate tumour heterogeneity, by accounting for the role of tumour-infiltrating immunecells, as well as immuno-inflammatory and cancer-associated fibroblasts.Objective 3: Develop a model calibration procedure with imaging data (provided by Prof. Evans and ProfThompson), aiming this way to capture the true boundaries of breast cancer tumours.Objective 4: Investigate analytically the models developed in Objectives 1 &2 via multiscale analysisconcepts such as three-scale convergence