Computational Modeling for Predicting 3D Cancer Cell Invasion into the Extracellular Fiber Network

用于预测 3D 癌细胞侵入细胞外纤维网络的计算模型

• 批准号: 1762961
• 负责人: Haruhiko Asada
• 金额: $ 39.62万
• 依托单位: Massachusetts Institute of Technology
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2021-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1762961&HistoricalAwards=false
• 关键词: Computational; Modeling; Predicting; 3D; Cancer

Physical interaction of a cell with the surrounding tissue is very important in cancer metastasis, wound healing, development, angiogenesis and many other normal and disease conditions. We still have only a small quantitative understanding of this for real tissues. One type of interaction that is not understood quantitatively is where a cell extends thin structures called a 'filopodia' that sense chemicals and "feel" the stiffness of the surrounding parts of the tissue. This research will create a three dimensional (3D) model of filipodia from the finest scale, to model the molecules in the 3D network of collagen fibers around the cell through the intermediate scale, where the molecules for viscoelastic mesh structures that undergo large deformations caused by the filopodia pushing and pulling on the network, and at the largest scale, model the migration of the cell as a coordinated activity of multiple filopodia, secretions of molecules that change the surrounding mesh and the pulling forces of the cell. This research will help to bring computational cell mechanics into the mainstream by building a 3D cell migration simulation software for researchers, educators, and students. The tools will be available as web tutorial modules and open software for educators, students, and researchers around the world. The project will also form a Forum of software users and research collaborators. This research project will further the goal of the United States to understand the activities of cells that contribute to health and disease of its citizens.This project's computational model will significantly advance the quantitative understanding of 3D cell invasion into the ECM fiber network. It will include cell-ECM interactions at the binding kinetics level and integrate the numerous key mechanisms into the modeling of whole cell-level migration. In vitro microfluidic experiments will be conducted to determine unknown parameters and verify the computational model. The resultant model will be used to predict how cell migration in 3D ECM is influenced by the stiffness and, also, ECM porosity, single fiber diameter, and cross-linker properties. It will be used to predict whether there is an optimal MMP secretion level for 3D cell invasion into ECM; too much secretion of MMP rapidly degrades the ECM fiber network and makes it too soft, while too little secretion of MMP impedes the cell to invade into ECM. A group of cells can communicate with one another through stress and strain propagation in the ECM and create migratory behaviors as a collective event. The emergent behavior of collective cell migration will be predicted using the multi-scale computational model.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

细胞与周围组织的物理相互作用在癌症转移、伤口愈合、发育、血管生成和许多其他正常和疾病状况中非常重要。对于真实的组织，我们仍然只有很少的定量了解。 一种无法定量理解的相互作用是细胞延伸称为“丝状伪足”的薄结构，该结构感测化学物质并“感觉”组织周围部分的硬度。 这项研究将从最精细的尺度创建丝状伪足的三维（3D）模型，以通过中间尺度模拟细胞周围胶原纤维的3D网络中的分子，其中粘弹性网状结构的分子经历由丝状伪足在网络上推拉引起的大变形，并且在最大尺度下，将细胞迁移建模为多个丝状伪足的协调活动，改变周围网格的分子分泌物和细胞的拉力。 这项研究将有助于通过为研究人员，教育工作者和学生构建3D细胞迁移模拟软件，将计算细胞力学纳入主流。这些工具将作为网络教程模块和开放软件提供给世界各地的教育工作者、学生和研究人员。该项目还将形成一个软件用户和研究合作者论坛。 该研究项目将进一步推进美国的目标，了解有助于其公民健康和疾病的细胞活动。该项目的计算模型将大大推进对ECM纤维网络中3D细胞入侵的定量理解。它将包括在结合动力学水平上的细胞-ECM相互作用，并将许多关键机制整合到整个细胞水平迁移的建模中。将进行体外微流控实验以确定未知参数并验证计算模型。所得到的模型将用于预测细胞迁移在3D ECM中如何受到刚度以及ECM孔隙率、单纤维直径和交联剂性质的影响。它将用于预测是否存在3D细胞侵入ECM的最佳MMP分泌水平; MMP分泌过多会迅速降解ECM纤维网络并使其过于柔软，而MMP分泌过少会阻碍细胞侵入ECM。一组细胞可以通过ECM中的应力和应变传播彼此通信，并作为集体事件产生迁移行为。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

A Robotic Microscope System to Examine T Cell Receptor Acuity Against Tumor Neoantigens: A New Tool for Cancer Immunotherapy Research

• DOI: 10.1109/lra.2019.2894466
• 发表时间: 2019-04-01
• 期刊: IEEE ROBOTICS AND AUTOMATION LETTERS
• 影响因子: 5.2
• 作者: Ong, Lee-Ling Sharon;Zhu, Hai;Asada, H. Harry
• 通讯作者: Asada, H. Harry

Computational modeling of three-dimensional ECM-rigidity sensing to guide directed cell migration

• DOI: 10.1073/pnas.1717230115
• 发表时间: 2018-01-16
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Kim, Min-Cheol;Silberberg, Yaron R.;Asada, H. Harry
• 通讯作者: Asada, H. Harry

Multi-cell ECM compaction is predictable via superposition of nonlinear cell dynamics linearized in augmented state space

通过在增强状态空间中线性化的非线性细胞动力学的叠加可以预测多细胞 ECM 压实

• DOI: 10.1371/journal.pcbi.1006798
• 发表时间: 2019
• 期刊: PLOS Computational Biology
• 影响因子: 4.3
• 作者: Mayalu, Michaëlle N.;Kim, Min-Cheol;Asada, H. Harry;Maini, Philip K
• 通讯作者: Maini, Philip K

Extracellular matrix remodelling induced by alternating electrical and mechanical stimulations increases the contraction of engineered skeletal muscle tissues

• DOI: 10.1038/s41598-019-39522-6
• 发表时间: 2019-02-25
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Kim, Hyeonyu;Kim, Min-Cheol;Asada, H. Harry
• 通讯作者: Asada, H. Harry

Modeling of Collective Cell Behaviors Interacting With Extracellular Matrix Using Dual Faceted Linearization

使用双面线性化对与细胞外基质相互作用的集体细胞行为进行建模

• DOI: 10.1115/dscc2018-9164
• 发表时间: 2018
• 期刊: 2018 ASME Dynamic Systems and Control Conference
• 作者: Mayalu, Michaëlle N.;Kim, Min-Cheol;Asada, H. Harry
• 通讯作者: Asada, H. Harry