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Physical Models for Cancer Progression

癌症进展的物理模型

基本信息

批准号：
1708128
负责人：
Devarajan Thirumalai
金额：
$ 70万
依托单位：
University of Texas at Austin
依托单位国家：
美国
项目类别：
Continuing Grant
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1708128&HistoricalAwards=false
关键词：
Physical Models Cancer Progression

项目摘要

The goal of this project is to use theoretical and computational tools to decipher general principles and to quantitatively describe tumor evolution. The PI will address two problems in cancer research: (a) how the interplay of distinct types of somatic mutations impacts tumor evolution and (b) what is the mechanism of origin of tumor heterogeneity. Solutions to these problems, which are relevant to all cancers, using physics-based models and analytical tools based on concepts in glass physics will be sought. The outcome of this work will provide a quantitative and integrated picture of a few key important issues in cancer research. The results will provide a platform for analyzing clinical data, as the initial studies already demonstrate. The PI will provide training of the next generation of students and postdoctoral research fellows in the area of theoretical research on cancer in which physics concepts and quantitative methods will play an increasing role. The training of these scientists will include sustained efforts to integrate the field of glass physics into cancer research.Two major issues will be investigated: (1) Role of beneficial passenger or mini-drivers mutations on cancer progression: According to the somatic mutation theory, cancer is caused by clonal expansion of cells due to accumulation of mutations over a life time that gives fitness advantage to tumor cells. Much of the focus has been on driver mutations as the cause of cancer, and very little attention has been paid to passenger mutation. The PI will use models that consider the interplay of driver mutations as well as deleterious and beneficial passenger mutations to obtain quantitative predictions for tumor evolution and cancer dormancy in terms of mutation rates, population size, and fitness of mutation types. (2) Physical models for Cancer Heterogeneity: There is a resurgent interest in understanding the origin of non-genetic cancer heterogeneity, although its importance in affecting cancer therapy was appreciated decades ago. Clarifying the origin of heterogeneity requires creating three dimensional models accounting for the birth and death of cells. In addition, the proposed models must include physical inter cellular forces, allowing us to quantify tumor microenvironment and its evolution with realistic dynamics. The PI will use two models that explicitly account for both spatial migration (characteristic of cells that have lost or have reduced E-cadherin expression) and adhesive forces as found in epithelial cells. The PI suggests that some of the theoretical concepts rooted in glass physics are necessary to fully understand cancer heterogeneity. The expected results will not only bridge the two fields but also provide a way to describe quantitatively the migration of cancer cells from their sites of origin to distant sites.

该项目的目标是使用理论和计算工具来破译一般原理并定量描述肿瘤演变。PI将解决癌症研究中的两个问题：（a）不同类型的体细胞突变的相互作用如何影响肿瘤演变和（B）肿瘤异质性起源的机制是什么。这些问题的解决方案，这是相关的所有癌症，使用基于物理学的模型和分析工具的基础上，在玻璃物理学的概念将寻求。这项工作的结果将提供一个定量和综合的图片在癌症研究中的一些关键的重要问题。正如最初的研究已经证明的那样，这些结果将为分析临床数据提供一个平台。PI将在癌症理论研究领域为下一代学生和博士后研究员提供培训，其中物理概念和定量方法将发挥越来越大的作用。本项目将研究两个主要问题：（1）有益的乘客或小驱动突变在癌症进展中的作用：根据体细胞突变理论，癌症是由于细胞在一生中积累突变，使肿瘤细胞具有适应性优势，从而导致细胞克隆扩增而引起的。大部分的焦点都集中在作为癌症原因的驱动突变上，很少关注乘客突变。PI将使用考虑驱动突变以及有害和有益乘客突变的相互作用的模型，以获得肿瘤演变和癌症休眠的突变率，群体大小和突变类型的适应性的定量预测。(2)癌症异质性的物理模型：人们对了解非遗传癌症异质性的起源重新产生了兴趣，尽管它在影响癌症治疗方面的重要性在几十年前就被认识到了。澄清异质性的起源需要创建三维模型来解释细胞的出生和死亡。此外，所提出的模型必须包括物理细胞间的力量，使我们能够量化肿瘤微环境及其演变与现实的动态。PI将使用两种模型，明确解释空间迁移（E-钙粘蛋白表达缺失或减少的细胞的特征）和上皮细胞中发现的粘附力。PI建议，一些植根于玻璃物理学的理论概念对于充分理解癌症异质性是必要的。预期的结果不仅将架起这两个领域的桥梁，而且还提供了一种定量描述癌细胞从起源地迁移到远处的方法。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A mathematical model for phenotypic heterogeneity in breast cancer with implications for therapeutic strategies

DOI：
10.1098/rsif.2021.0803
发表时间：
2022-01-26
期刊：
JOURNAL OF THE ROYAL SOCIETY INTERFACE
影响因子：
3.9
作者：
Li, Xin;Thirumalai, D.
通讯作者：
Thirumalai, D.

Adhesion strength between cells regulate nonmonotonic growth by a biomechanical feedback mechanism

细胞之间的粘附强度通过生物力学反馈机制调节非单调生长

DOI：
10.1016/j.bpj.2022.04.032
发表时间：
2022
期刊：
Biophysical Journal
影响因子：
3.4
作者：
Malmi-Kakkada, Abdul N.;Sinha, Sumit;Li, Xin;Thirumalai, D.
通讯作者：
Thirumalai, D.

Origin of superdiffusive behavior in a class of nonequilibrium systems

一类非平衡系统中超扩散行为的起源

DOI：
10.1103/physreve.99.032401
发表时间：
2019
期刊：
Physical Review E
影响因子：
2.4
作者：
Samanta, Himadri S.;Thirumalai, D.
通讯作者：
Thirumalai, D.

Spatially heterogeneous dynamics of cells in a growing tumor spheroid: comparison between theory and experiments

肿瘤球体生长中细胞的空间异质动力学：理论与实验的比较

DOI：
10.1039/c9sm02277e
发表时间：
2020
期刊：
Soft Matter
影响因子：
3.4
作者：
Sinha, Sumit;Malmi-Kakkada, Abdul N.;Li, Xin;Samanta, Himadri S.;Thirumalai, D.
通讯作者：
Thirumalai, D.

Share, but unequally: a plausible mechanism for emergence and maintenance of intratumour heterogeneity