The Allee Effect in Tumor Initiation

肿瘤发生中的 Allee 效应

基本信息

批准号：
10334470
负责人：
Amy Brock
金额：
$ 43.92万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-07 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10334470
关键词：
Aging Behavior Biological Breast Cancer cell line Carrying Capacities Cell Communication Cell Culture Techniques Cell Proliferation Cells Collection Communication Communities Complement Data Dissection Ecosystem Epigenetic Process Exercise Experimental Designs Formulation Foundations Gene Expression Profile Goals Graph Growth Growth Factor Heterogeneity Individual Indolent Joints Kinetics Lesion Ligands Link Malignant Neoplasms Mammalian Cell Maps Mathematics Measurement Measures Mediating Microscopic Modeling Monitor Nutrient Oligonucleotides Oxygen Paracrine Communication Population Population Density Population Growth Population Sizes Prostate Regulation Resolution Resources Role Signaling Molecule Statistical Data Interpretation Structure Systems Biology Thyroid Gland Tissues Tumor Biology Tumor Cell Line anticancer research autocrine base cancer cell cancer heterogeneity cancer stem cell cell dimension fitness in vivo mathematical model member neoplastic cell novel paracrine phenomenological models prevent real time monitoring receptor receptor expression resilience single cell analysis statistics theories tool transcriptome sequencing transcriptomics tumor tumor growth tumor heterogeneity tumor initiation

项目摘要

SUMMARY In ecosystem modeling, the Allee effect describes a correlation between population size (number of members) and mean fitness (proliferation rate) of individuals. Increased proliferation with increased population size implies cooperative interactions. A contrasting principle in ecosystems is population “carrying capacity” which describes a decrease in growth rates with increasing population size, due to competition for limited resources. While the concept of carrying capacity has been studied in tumors (which may become limited in nutrients or oxygen), the Allee effect has been almost entirely overlooked. Allee effects are significant in small populations and thus may be critical to understanding the earliest steps in tumor iniation. To investigate the fundamental contribution of the Allee effect on tumor ecosystems requires the novel experimental designs and integration of quantitative experimental measurements with mathematical modeling. The overall goal of this project is to dissect the contribution of population size and cell-cell communication in a few selected, well-suited tumor cell lines through quantitative single-cell resolution, real-time monitoring of cell populations. Mathematical models of growth kinetics will show that the Allee effect and cell-cell communication has consequences on a single cancer cell’s decision to initiate a growing tumor or to stay dormant. These communication networks will be further mapped by identification of specific paracrine factors and receptors. Disruption of the communication network that establishes a proliferative tumor will be performed by targeting specific cell subpopulation interactions. Perturbations will include depletion of specific cell subtypes, manipulation of overall paracrine signaling, and blocking of specific ligand-receptor combinations on interacting species. These strategies may be novel tools to trigger tumor cell population collapse. Population-level effects in a nascent tumor population have not been quantitatively explored and may explain the phenomenon of critical thresholds and define a mechanistic role for intratumor heterogeneity. This project focuses on a fundamental generic principle that is broadly applicable in many contexts and thus could complement and enrich the modeling efforts of the cancer research community.

概括在生态系统建模中，Allee效应描述人口规模（成员数量）之间的相关性和个体的平均健身（增殖率）。增加人口规模的增殖增加暗示合作互动。生态系统中的一种对比原则是人口“承载能力” 由于资源有限的竞争，描述了随着人口规模的增加，增长率的下降。虽然已经在肿瘤中研究了承载能力的概念（可能受到营养或氧气），几乎完全忽略了Allee效应。小人群中的Allee效应很重要因此，对于理解肿瘤的最早步骤可能至关重要。调查基本 Allee对肿瘤生态系统的贡献需要新颖的实验设计和整合数学建模的定量实验测量。该项目的总体目标是在少数选定的，合理的肿瘤细胞中剖析了种群大小和细胞通信的贡献通过定量单细胞分辨率的线，对细胞种群的实时监测。数学模型生长动力学将表明Allee效应和细胞 - 细胞通信对单个癌细胞决定启动肿瘤或处于休眠状态的决定。这些通信网络将是通过识别特定的偏眼厂和接收器的识别进一步映射。沟通的破坏建立增殖肿瘤的网络将通过靶向特定的细胞亚群来执行互动。扰动将包括特定细胞亚型的耗竭，操纵整体旁分泌信号传导，并阻止相互作用物种上特定的配体 - 受体组合。这些策略可能是触发肿瘤细胞种群崩溃的新工具。肿瘤种群中的种群水平影响尚未被定量探索，可以解释临界阈值的现象并定义肿瘤内异质性的机械作用。该项目侧重于一个基本的通用原则广泛适用于许多情况，因此可以完成并丰富癌症的建模工作研究社区。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Phenotypic Basis for Matrix Stiffness-Dependent Chemoresistance of Breast Cancer Cells to Doxorubicin.

DOI：
10.3389/fonc.2018.00337
发表时间：
2018
期刊：
Frontiers in oncology
影响因子：
4.7
作者：
Joyce MH;Lu C;James ER;Hegab R;Allen SC;Suggs LJ;Brock A
通讯作者：
Brock A

Integrating Quantitative Assays with Biologically Based Mathematical Modeling for Predictive Oncology.

DOI：
10.1016/j.isci.2020.101807
发表时间：
2020-12-18
期刊：
iScience
影响因子：
5.8
作者：
Kazerouni AS;Gadde M;Gardner A;Hormuth DA 2nd;Jarrett AM;Johnson KE;Lima EABF;Lorenzo G;Phillips C;Brock A;Yankeelov TE
通讯作者：
Yankeelov TE

Cancer cell population growth kinetics at low densities deviate from the exponential growth model and suggest an Allee effect